SpringerBriefs in Applied

Sciences and Technology

Nanotheranostics

Series Editors
Subramanian Tamil Selvan
Institute of Materials Research and Engineering,
National University of Singapore, Singapore,
Singapore

Karthikeyan Narayanan
Singapore, Singapore

Padmanabhan Parasuraman
Singapore, Singapore

Paulmurugan Ramasamy
Stanford University School of Medicine, Palo Alto,
CA, USA

Indexed by SCOPUS. Nanotheranostics is a

burgeoning field in recent years, which makes use of
“nanotechnology” for diagnostics and therapy of
different diseases. The recent advancement in the
area of nanotechnology has enabled a new
generation of different types of nanomaterials
composed of either inorganic or polymer based
nanoparticles to be useful for nanotheranostics
applications. Some of the salient features of the
nanotechnology towards medicine are cost
reduction, reliable detection and diagnosis of
diseases at an early stage for optimal treatment. The
advent of nanotheranostics is expected to benefit the
pharmaceutical and healthcare industries in the next
5-10 years. Nanotechnology holds a great potential
to be explored as a multifunctional platform for a
wide range of biological and engineering
applications such as molecular sensors for disease
diagnosis, therapeutic agents for the treatment of
diseases, and a vehicle for delivering therapeutics
and imaging agents for theranostic applications in
cells and living animals.
Tamil Selvan Subramanian

Nanomedicine
Emerging Prospects
Tamil Selvan Subramanian
Alpha Biomedical Pte. Ltd., Singapore, Singapore

ISSN 2191-530X e-ISSN 2191-5318

SpringerBriefs in Applied Sciences and Technology
ISSN 2197-6740 e-ISSN 2197-6759
Nanotheranostics
ISBN 978-981-99-2138-6 e-ISBN 978-981-99-2139-
3
https://doi.org/10.1007/978-981-99-2139-3

© The Editor(s) (if applicable) and The Author(s),

under exclusive license to Springer Nature
Singapore Pte Ltd. 2023

This work is subject to copyright. All rights are solely

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Contents
1 Introduction to Nanomedicine
1.​1 Nanomedicine
1.​1.​1 Nanomaterials for Cancer
Nanomedicine
1.​2 Challenges and Advancements of
Nanomaterials for Nanomedicine
1.​2.​1 Nanomedicine Advancements in
Cancer and Neurodegenerativ​e Diseases
1.​2.​2 Nanomedicine Advancements in
Orthopaedics and Cardiovascular Diseases
References
2 Cancer Nanomedicine
2.​1 Emerging QDs and NPs as Bioimaging
Probes
2.​1.​1 NIR Emitting QDs for Deep-Tissue
Bimodal Imaging
2.​1.​2 Au-NPs and Tripods for Bioimaging
and Therapy
2.​2 NPs as Drug Carriers
2.​2.​1 Iron Oxide NPs
2.​2.​2 Silica-Based Carriers
2.​2.​3 Graphene and Graphene Oxide as
Carriers
 2.​2.​4 Peptide/​Polymer Mediated Delivery
2.​2.​5 Liposomes for Targeted Delivery
2.​3 Photothermal Therapy
References
3 Nanomedicine for Neurodegenerativ​e
Diseases
3.​1 Design of NPs for Inhibiting Protein
Aggregation
3.​1.​1 Au NPs
3.​1.​2 Ceria NPs
3.​2 NP-Based Drug Delivery Carriers
3.​2.​1 Apolipoprotein
3.​2.​2 Dendrimers, Peptides, and Inorganic
NPs
3.​3 NP-Based Biosensors for AD Diagnosis
References
4 Nanomedicine for Orthopaedics
4.​1 Nanoscale Materials for Bone Tissue
Regeneration
4.​1.​1 Natural Polymers Based Scaffolds for
Bone Regeneration
4.​1.​2 Hydroxyapatite and Graphene Oxide
Scaffolds for Bone Regeneration
 4.​1.​3 Antibacterial Nanoparticles Coated
Orthopaedic Implants
4.​2 Hydrogel Scaffolds for Osteogenic
Differentiation of Stem Cells
4.​2.​1 Polymer/​Stem Cells Implanted
Hydrogels for Cartilage Regeneration
4.​3 Nanomedicine for Controlled
Orthopaedic Drug Delivery
References
5 Nanomedicine for Cardiac Diseases
5.​1 Nanomedicine for Diagnostics and
Therapeutics of CVDs
5.​1.​1 Nanomedicine for Cardiac Tissue
Repair and Reinforcement
5.​1.​2 Nanocarriers for Cardiac Delivery of
Drugs and MicroRNA
5.​2 Nanotechnology Assisted Cardiac
Regenerative Medicine
5.​2.​1 Dextran NPs Assisted Dual Drug
Delivery for Cardiac Regeneration
5.​2.​2 Nanotherapeutic Approach for
Alleviating Cardiac Brain Injury
5.​2.​3 Nanoparticle-Based Composite Patch
for Myocardial Infarction
References
6 Conclusions and Perspectives
References
© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2023
S. Tamil Selvan, Nanomedicine, Nanotheranostics
https://doi.org/10.1007/978-981-99-2139-3_1

1. Introduction to
Nanomedicine
Subramanian Tamil Selvan 1
(1) Alpha Biomedical Pte. Ltd., Singapore,
Singapore

Subramanian Tamil Selvan

Email: [email protected]

Abstract
A brief introduction is given to nanomedicine, an
emerging paradigm intersecting two burgeoning
fields of nanotechnology and medicine. It covers the
application of nanomedicine in diagnostics and
therapy of a wide range of diseases such as cancer,
cardiovascular, orthopaedics, and neurodegenerative
disorders. A wide range of nanomaterials,
nanoparticles and biomaterials for these applications
are discussed.

Keywords Nanoparticles – Nanomedicine – 2D

nanomaterials – Quantum dots – Diagnostics –
Therapy – Cancer – Neurodegenerative disorders –
Cardiovascular diseases – Orthopaedics
1.1 Nanomedicine
Nanomedicine is a field of interdisciplinary science
that integrates physical, chemical, and engineering
sciences, utilizing nanotechnology (functional
nanomaterials, and structures at the nanometer
scale between 1 and 100 nm) and medicine (drugs,
imaging tools and delivery devices) for disease
diagnosis and therapy.
Today, nanomedicine is a buzzword for a variety
of diseases including cancer (Chow and Ho 2013;
Min et al. 2015; Chen et al. 2017; Liu et al. 2017;
Nam et al. 2019), cardiovascular (PA Ferreira et al.
2015; Di Mauro et al. 2016), orthopaedics (Mazaheri
et al. 2015; Perli et al. 2017), dental (Besinis et al.
2015; Padovani et al. 2015; Chieruzzi et al. 2016;
Priyadarshini et al. 2016; Fawzy et al. 2017;
Priyadarshini et al. 2017), kidney (Marom et al.
2012; Kamaly et al. 2016; Williams et al. 2016), and
neurodegenerative diseases (Goldsmith et al. 2014;
Saraiva et al. 2016; Tapeinos et al. 2017; Teleanu et
al. 2019a).

1.1.1 Nanomaterials for Cancer

Nanomedicine
In cancer nanomedicine, a wide range of
nanomaterials including two-dimensional 2D
MoS2/Bi2S3 (Liu et al. 2014; Wang et al. 2015a, b;
Song et al. 2016), MnO2 nanosheets (Chen et al.
2014f), graphene oxide (Chen et al. 2014e),
transition metal dichalcogenide nanomaterials (Gong
et al. 2017) have been developed extensively for
therapeutic and diagnostic (i.e. theranostics)
applications of cancer (Peng et al. 2017).
Nanotechnology assisted approaches for stem cell
differentiation, tracking, labelling, and therapy have
been delineated in recent reviews by our group
(Nanda et al. 2017; Yi et al. 2017).
Different nanoparticles (NPs) have been designed
for nanomedicine over the last decade. Metallic NPs
(e.g. Au, Ag, Pd, Pt, Cu) have been used as
plasmonic nanosensors or surface-enhanced Raman
scattering (SERS) probes for label-free ultrasensitive
molecular detection of body fluids (Kosaka et al.
2014; Bui et al. 2015; Lane et al. 2015; Langer et al.
2015; Jeong et al. 2016; Yang et al. 2016b; Xie et al.
2017). Conversely, semiconductor quantum dots
(QDs) have been extensively used for biological
applications (Mattoussi et al. 2000; Gao et al. 2004;
Medintz et al. 2005; Chang and Rosenthal 2012).
Despite toxicity issues related to heavy metal
cadmium, even today, semiconducting NPs such as
CdSe/ZnS QDs are the best diagnostic agents for in-
vitro cell labelling and in-vivo animal imaging
studies, thanks to their excellent optical properties
and stabilities (Yen and Selvan 2015; Freyer et al.
2019; Hanifi et al. 2019; Ondry et al. 2019) Alternate
non-cadmium based QDs have emerged in response
to combat heavy metal Cd-based cytotoxicity (Xu et
al. 2016). For example, Mn-doped ZnS QDs have
been used as protein sensors (Wu et al. 2013), used
for detection of H2S (Wu et al. 2014) and dopamine
(Diaz-Diestra et al. 2017) in biological samples, and
as imaging probes for intracellular Zn2+ ions (Ren et
al. 2011). Earlier, our group contributed to the
grafting of Mn-doped ZnS nanocrystals and
anticancer drug (doxorubicin) onto graphene oxide
for cell labelling and delivery (Dinda et al. 2016).
Conversely, molybdenum disulfide QDs (Liu et al.
2018) has been used for the detection of dopamine.
Recently, ZnO nanowires and nanocomposites
(e.g., Ag–ZnO) have shown great potentials in the
detection of cancer biomarkers such as RNA, DNA,
proteins, and extracellular vesicles (Guo et al. 2018;
Paisrisarn et al. 2022; Chattrairat et al. 2023; Huang
et al. 2023; Jung et al. 2023). It is worth mentioning
here the application of ZnO and TiO2 nanostructures
for the biosensing of proteins using the surface-
enhanced Raman scattering (SERS) approach
(Adesoye and Dellinger 2022).
Multifunctional NPs for multimodal bioimaging
incorporating optical imaging using NIR emitting
QDs or up-conversion luminescence, computed
tomography (CT) and magnetic resonance imaging
(MRI), and therapy (Lee et al. 2012) (photodynamic,
photothermal, targeted drug delivery (Liu et al.
2015), pH‐triggered on‐demand drug release (Wang
et al. 2015c) etc.), have attracted immense interest
(Chen et al. 2014d; Wu et al. 2015; Li and Chen
2016; Duan et al. 2017; Amirav et al. 2019). We have
also pioneered the synthesis of bifunctional
nanomaterials (fluorescent QDs, magnetic iron
oxide, up-conversion, and magnetic/antibacterial
NPs) for bimodal imaging (optical and MRI) and
therapeutic applications (Selvan et al. 2007; Ang et
al. 2009; Selvan et al. 2009; Das et al. 2010; Selvan
2010; Zhang et al. 2014). Carbon nanodots (Bhunia
et al. 2013; Shi et al. 2015; Xu et al. 2015) and
graphene QDs (Zhang et al. 2012; Zheng et al.
2015a, b; Yang et al. 2016a; Yao et al. 2016; Yan et
al. 2019) have been extensively explored as
bioimaging probes. Interestingly, carbon dots have
recently emerged as a potential candidate system in
nanomedicine to protect the cells from oxidative
stress, eliminating intracellular reactive oxygen
species (ROS) (Xu et al. 2015). It is worth
mentioning here the use of ceria–zirconia NPs as a
therapeutic nanomedicine for treating ROS-related
inflammatory diseases such as sepsis (Soh et al.
2017). Several ROS-mediated nanomedicine systems
have been delineated recently (Yang et al. 2019;
Ding et al. 2023; Naik and David 2023).
Notable advances have been made in the
synthesis of different magnetic NPs (MNPs) (e.g.,
Fe3O4, Fe2O3, FePt, Co), and their nanostructures
and composites. (Yen et al. 2013b; Yen et al. 2015;
Kang et al. 2017; Wang et al. 2018; Yang et al. 2018;
Ray et al. 2019; Satpathy et al. 2019; Esthar et al.
2023; Liu et al. 2023).
These magnetic nanocomposites can be used as
drug carriers (Farmanbar et al. 2022; Turrina et al.
2022; Esthar et al. 2023; Liu et al. 2023),
hyperthermia agents (Ansari et al. 2022; Shabalkin
et al. 2023), and MRI contrast agents (Cheraghali et
al. 2023; Jiang et al. 2023) in cancer
diagnosis/bioimaging (Mohapatra et al. 2023) and
therapy (Su et al. 2023; Vangijzegem et al. 2023).
Iron oxide NPs combined radioisotopes (e.g., Tc-
99 m) can be used as dual modality contrast agents
for the high spatial resolution of MRI applications
combined with high sensitivity single photon
emission computed tomography (SPECT), and
positron emission tomography (PET) (Karageorgou
et al. 2023).
Upconversion NPs (UCNPs) (e.g. NaYF4:Er,
NaGdF4:Er) are another interesting class of
materials utilized extensively for bioimaging, owing
to their stable luminescence; and fabricated as core–
shell NPs (Dou et al. 2015) or multifunctional NPs
for bioimaging, and photodynamic therapy (PDT)
(Idris et al. 2012; Chen et al. 2014a; Wang et al.
2015b; Zhou et al. 2015; Zhou et al. 2016; Xu et al.
2017; Liu et al. 2019b; Zhang et al. 2019). Other
polymeric NPs (Ang et al. 2014), hybrid NPs
(Nguyen and Zhao 2015; Zhang et al. 2017), and
multifunctional NPs derived from small organic
building blocks (Xing and Zhao 2016) have
considerably contributed to nanomedicine.
Conversely, rare-earth oxide NPs (e.g. gadolinium
oxide) found their potential uses in MRI and
chemotherapy (Wu et al. 2019).
Although metallic NPs such as Au, Ag are
synthesized in water directly, most of other NPs such
QDs, UCNPs, MNPs are synthesized in presence of
organic ligands at temperatures over 200 °C,
resulting in hydrophobic NPs. Different coating
methods have been developed to make these
hydrophobic NPs water soluble. Today, the
stabilization of NPs in water and biological media
has become a matured strategy, thanks to a wide
variety of coating strategies that exist in the
literature. This includes silica (Mulvaney et al. 2000;
Gerion et al. 2001; Selvan et al. 2004; Darbandi et
al. 2005; Selvan et al. 2005; Yi et al. 2005; Zhelev et
al. 2006; Tan et al. 2007), polymer (Hong et al. 2012;
Wang et al. 2013; Yen et al. 2013a; Chen et al.
2014b; Topete et al. 2014; Palui et al. 2015),
peptides (Narayanan et al. 2013; Chen, Li et al.
2014c; Yang et al. 2017; Zhang et al. 2018),
lipids/liposomes (Medintz et al. 2005; Murcia et al.
2008; Weng et al. 2008; Al-Jamal et al. 2009; Tian et
al. 2011), proteins (Mattoussi et al. 2000; Chithrani
and Chan 2007; Yang et al. 2013; Hu et al. 2014; Tay
et al. 2014; Sasaki et al. 2015; Scaletti et al. 2018),
antibodies (Goldman et al. 2002; Medintz et al. 2005;
Snyder et al. 2009), and enzymes (Kong et al. 2016)
for the stabilization of NPs. Hydrophobic ligands
such as HDA can also be used for the stabilization of
Au NRs and heterostructures (Cheng et al. 2014; He
et al. 2014).

1.2 Challenges and Advancements of

Nanomaterials for Nanomedicine
In general, nanomaterials in biomedical applications
pose an important concern: what are the safety
concerns of nanomaterials? How do we address the
growing needs of ageing population with
neurodegenerative disorders, and early diagnosis
and therapeutic measures for diseases like cancer?
This Book attempts to address the above concerns
with the advent of nanomedicine. Compared to
cancer nanomedicine, the application of
nanomedicine in neurodegenerative diseases is still
in its infancy state. The biggest challenge in
neurodegenerative diseases is to tackle the
permeability of blood-brain-barrier (BBB) and deliver
therapeutic drugs to the brain (Ramanathan et al.
2018). Toward this goal, nanoscale materials have
been developed and used either as bio-labelling
agents or as therapeutic carriers, and in some cases
as neuroprotective agents for neurodegenerative
diseases (Goldsmith et al. 2014; Saraiva et al. 2016;
Teleanu et al. 2019b; Liu et al. 2019a; Le Floc’h et
al. 2019).
This Brief focuses mainly on the application of
nanomedicine in cancer and neurodegenerative
diseases. It also attempts to cover the application of
nanomedicine in other emerging areas such as
orthopaedics, and cardiac diseases (Fig. 1.1).
Fig. 1.1 Applications of nanomedicine in cancer,
orthopaedics, neurodegenerative, and cardiac diseases

1.2.1 Nanomedicine Advancements in

Cancer and Neurodegenerative
Diseases
Some of the recent advancements (See Chap. 2) in
cancer diagnosis (e.g., multimodal tumor imaging)
and therapy (e.g., combined therapies involving
either photothermal, chemotherapy, photodynamic
or immunotherapy) have been made using 2D
nanomaterials (Chen et al. 2020; Ding et al. 2020)
(e.g., MoS2/Bi2S3 nanocomposites (Wang et al.
2015a; Wang et al. 2019), molybdenum oxide
nanosheets (Song et al. 2016; Wang et al. 2023b),
MoS2 nanosheets (Liu et al. 2014; Murugan and Park
2023), MnO2 nanomaterials (Chen et al. 2014f; Tan
et al. 2017; Ding et al. 2020), doped graphene
nanosheets (Lu et al. 2022), graphene oxide‐based
multifunctional nanomaterials (Gonçalves et al.
2013; Chen, Xu et al. 2014e; Gu et al. 2019; Itoo et
al. 2022), and multifunctional Au-based
nanomaterials (Ouyang et al. 2023; Wang et al.
2023c), and magnetic nanomaterials (Mukherjee et
al. 2020; Liu et al. 2021).
Chapter 3 deals with different nanomedicine
approaches for neurodegenerative diseases such as
Alzheimer’s disease (AD). Design of inorganic NPs
(e.g., Au, ZnO, MoS2, CeO2) and organic NPs (e.g.,
curcumin, green tea polyphenol- EGCG) for
inhibiting the amyloid aggregation and tau
hyperphosphorylation associated with the AD are
discussed (Han et al. 2017; Shukla et al. 2021; Tamil
Selvan et al. 2021). Different NP-based drug delivery
approaches (e.g., apolipoprotein, peptides,
dendrimers) to the delivery of CNS drugs across the
blood–brain barrier (BBB) are also discussed
(Tapeinos et al. 2017; Arvanitis et al. 2020; Loch et
al. 2023).

1.2.2 Nanomedicine Advancements in

Orthopaedics and Cardiovascular
Diseases
Chapter 4 addresses nanomedicine and tissue
engineering approaches for orthopaedics. Bone
mimicking scaffolds composed of polymers (e.g.,
polycaprolactone, polylactic acid, chitosan) and
inorganic nanomaterials (e.g., reduced graphene
oxide rGO, hydroxyapatite) (Seyedsalehi et al. 2020),
and zwitterionic chitosan/β-tricalcium phosphate
hydrogel/GO scaffolds (Wang et al. 2023a) for bone
tissue engineering applications are covered.
Orthopaedic drug delivery systems using dextran/β-
tricalcium phosphate nanocomposite hydrogel
scaffolds (Ghaffari et al. 2020), and chitosan-
vancomycin hydrogel bone repair scaffold (Gao et al.
2023) are also delineated.
Chapter 5 delineates the applications of
nanomedicine in diagnostics and treatment of
cardiovascular diseases (CVDs). Recent
developments in multifunctional NPs (Kleinstreuer et
al. 2018), nano/biomaterials and devices to diagnose
and treat a variety of CVDs with the attributes of
mechanical, conductive, and biological requirements
are discussed (Liu et al. 2020; Saeed et al. 2023).
Chapter 6 provides conclusions and perspectives
on different types of emerging nanomaterials and
NPs as theranostic tools for cancer,
neurodegenerative, orthopaedic, and cardiac
diseases.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte
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S. Tamil Selvan, Nanomedicine, Nanotheranostics
https://doi.org/10.1007/978-981-99-2139-3_2

2. Cancer Nanomedicine
Subramanian Tamil Selvan 1
(1) Alpha Biomedical Pte. Ltd., Singapore,
Singapore

Subramanian Tamil Selvan

Email: [email protected]

Abstract
This chapter deals with emerging QDs and NPs that
can be utilized as bioimaging probes for cancer
nanomedicine. It covers topics on deep-tissue
bimodal imaging utilizing NIR emitting QDs and
other interesting Au-NPs and tripods for bioimaging
and therapy. Drug carriers such as iron oxide NPs,
silica-, graphene-, graphene oxide- based
nanocarriers, peptides or polymer mediated delivery
vehicles, and liposomes for targeted delivery are
discussed. Metallic nanostructures and plasmonic
bimetallic nanocrystals and core–shell
nanocomposites for combined photothermal-/chemo-
or radio-/chemo-therapy are delineated.
Keywords Cancer – Bioimaging – Therapy –
Nanoparticles – Nanomedicine – Targeted delivery –
Diagnostics – Photothermal therapy

Cancer is one of the leading causes of human death

throughout the globe. Toward combating cancer,
tremendous efforts put forward in recent years in
drug discovery and pharmacological research.
However, a complete cure is beyond the reality. As a
thumb rule, prevention is better than cure. Despite
the fact that the Food and Drug Administration
(FDA) have approved several drugs, cisplatin and
derivatives are still considered as one of the
promising therapeutic strategies for cancer (Ruiz-
Ceja and Chirino 2017). Although the drugs are
capable of targeting the epidermal growth factor
receptor (EGFR), none of the pharmacological
treatments succeeded in the complete cure of cancer
even in combination with radiation and surgery.
Therefore, the early detection of cancer biomarkers
is mandatory, for which nanotechnology is an
interesting approach. Here, a plethora of questions
arises: How do we achieve early diagnosis? How do
we deliver approved drugs more specifically to
cancer cells? What are their side effects? Would they
affect normal, non-cancerous cells?
In drug discovery and pharmacological research,
thiazolo[4,5-d]pyrimidines emerge as immune-
modulators, anticancer, anti-Parkinson’s,
antibacterial, antiviral, and antifungal agents
(Kuppast and Fahmy 2016). Furthermore, several
drug candidates such as pyrazole based compounds
with lesser side effects and improved efficacy are
being explored (Ganguly and Jacob 2017).
Microtubule-stabilizing agents/drugs have attracted
interest in clinical drug discovery, cancer therapy
studies (Zhao et al. 2016), and neurodegenerative
diseases (Brunden et al. 2017).
The interplay between nanotechnology and
medicinal chemistry has created new avenues in the
nanocarrier formulations (Sunoqrot et al. 2017).
Various drug delivery vehicles based on nanocarrier
formulations such as polymeric micelles (Nasongkla
et al. 2006; Gong et al. 2012; Kataoka et al. 2012),
liposomes (Hwang et al. 2016; Malinge et al. 2017;
Man et al. 2019), and polymer/inorganic NPs for
anticancer drug/siRNA delivery (Zhang et al. 2011;
Meng et al. 2013; Qu et al. 2019) have been explored
to increase the drug solubility, and bioavailability.
Cancer nanomedicine has advanced significantly
in recent years (Ali et al. 2017; Komatsu 2023).
Molecular imaging has advanced cancer
nanomedicine by integrating different multimodality
techniques such as MRI, near-infrared optical
imaging, positron emission topography (PET),
computed tomography (CT), etc. (Pratt et al. 2016;
Dearling and Packard 2017; Liu et al. 2017a; Miller
et al. 2017).

2.1 Emerging QDs and NPs as

Bioimaging Probes
Both CdSe/ZnS—based QDs and iron oxide (Fe3O4 or
Fe2O3) NPs dominated the bioimaging arena
especially in optical and MR imaging, respectively.
Although CdSe/ZnS QDs have been used extensively
as cell labelling probes, the presence of heavy
metals poses issues related to toxicity.
This section deals with the emergence of silver
based QDs (Ag2S, Ag2Se), up-conversion NPs
(UCNPs), Au-NPs, and their fabrication as either
bimodal or trimodal agents for biosensing and
imaging.

2.1.1 NIR Emitting QDs for Deep-

Tissue Bimodal Imaging
Bioimaging probes in the near-infrared window II
(NIR-II, 1000–1700 nm) are highly promising for in
vivo imaging with enhanced resolution and deeper
tissue penetration. Earlier, Ag2Se QDs synthesized in
the size regime of 2–3 nm exhibited the emission
wavelengths in the range of 700–820 nm, depending
on the size (Gu et al. 2011). This work also
elucidated the promise of these less toxic NIR
emitting Ag2Se QDs for deep-tissue in vivo imaging
of a nude mouse after abdominal injection and
detection on its backside.
In another interesting work, similar Ag2Se QDs
have demonstrated their potentials in trimodality
imaging, encompassing fluorescence, MRI, and PET
(Tian et al. 2019). This work further suggested that a
high tumor‐to‐muscle ratio of nine in PET imaging
achieved after conjugation of the particles with a
targeting peptide. Finally, the QDs excreted within
12 h from the body by the kidneys. Alternatively,
Ag2S QDs can be used as sensors for fluoride ions
detection in living cells (Hong et al. 2012; Hong et
al. 2017). These NIR emitting Ag2S QDs (emission at
795 nm) showed good sensitivity for F− detection
with a detection limit of 1.5 μM (Ding et al. 2017).
Very recently multifunctional NPs combining
photoluminescent PbS/CdS QDs (emitting in the
second biological window of 1000–1350 nm; 14 mm
deep-tissue imaging) and superparamagnetic Fe3O4
NPs (higher T2 relaxivity, 282 mM–1 s–1) have been
developed for in vivo bimodal imaging (MR and
optical), and bimodal therapy (based on magneto-,
and photo-thermal heating) (Yang et al. 2019).

2.1.2 Au-NPs and Tripods for

Bioimaging and Therapy
Au-NPs can act as QDs when they exist in the form of
clusters (Yahia-Ammar et al. 2016; Khandelwal and
Poddar 2017). Such Au22 clusters were synthesized,
thanks to the facile thiol conjugation chemistry (Yu
et al. 2014; Pyo et al. 2015). Ultra-bright Au22
clusters functionalized with thiolate ligands such as
glutathione yielded high photoluminescence (PL)
quantum yield (QY) (> 60%) in toluene after
rigidifying the Au-shell with tetraoctylammonium
(TOA) cations. However, transferring the clusters
back to water decreased the PL-QY to < 10. This
method warranted a facile phase transfer approach
to retain the high PL-QY. Interestingly, the same
group reported folate-functionalized Au22 clusters
(Au22-FA) with a PL-QY of 42%, enabling them for
imaging of HeLa cancer cells (Pyo et al. 2017).
Essentially, gold nanoclusters (Au NCs) provide
several key features such as non-toxicity, high renal
clearance (Chen et al. 2016), passive tumor
targeting (Liu et al. 2013), light induced cell death
(Zhang et al. 2015), drug delivery carriers (Yahia-
Ammar et al. 2016), and optical sensing and
biodetection (Shang et al. 2013), making them more
useful for cancer nanomedicine.
Earlier, Xing et al. developed an intriguing
trimodal nanoprobe, consisting of up-conversion
NPs, and Au-NPs encapsulated within silica
(NaY(Gd)F4:Yb3+/Er3+/Tm3+@SiO2-Au) for
multimodality imaging (fluorescence, MR and CT) of
tumor bearing mice in vivo (Xing et al. 2012). This
approach enabled for ameliorating contrast effects
necessary for in vivo optical, MR and CT imaging,
owing to the presence of up-conversion NPs for
optical, Gd ions for T1 MR contrast, and Au NPs for
CT.
Nano Au tripods have been studied for molecular
imaging of living subjects, utilizing positron emission
tomography (PET) and photoacoustic (PA) imaging
modalities (Cheng et al. 2014). We have recently
developed Cu–Au tripods for photothermal
anticancer therapy (Nanda et al. 2019) Some of the
typical examples of NPs serving as bioimaging
probes are shown in Fig. 2.1. In our group,
bifunctional NPs (MNP@Dye-Pol) consisting of
magnetic iron oxide NPs (MNPs) and IR-820 dye
functionalized with an amphiphilic polymer, poly-
(isobutylene-alt-maleic anhydride) for NIR cell
imaging and MR animal imaging have been
developed (Fig. 2.1a) (Yen et al. 2013). Conversely,
tripod Au NPs have been used for PET and PA animal
imaging (Fig. 2.1b) (Cheng et al. 2014). Therapeutic
applications employing NPs of different shapes (e.g.
tripods, (Nanda et al. 2019) and nanoprisms (Pérez-
Hernández et al. 2014; Zhou et al. 2014a). Pérez-
Hernández et al. (2015) have been demonstrated
(Fig. 2.1c, d). The interplay of NPs between imaging
and therapy is depicted in a cartoon (Fig. 2.1e).

Fig. 2.1 Schematic representation of nanoparticles (NPs)

used in cell labelling, animal imaging, and therapeutic
application. a Bimodality imaging of NIR-dye@polymer—
conjugated magnetic NPs for optical and magnetic
resonance imaging. Reproduced with permission (Yen et al.
2013). Copyright 2013, ACS. b Au-tripod for PET and PA
imaging. Reproduced with permission (Cheng et al. 2014).
Copyright 2014, ACS. c Photothermal conversion efficiency
endowed by Cu–Au tripod nanocrystals. Reproduced with
permission (Nanda et al. 2019). Copyright 2019, ACS. d Au-
nanoprisms for NIR-assisted cancer therapy. Reproduced
with permission (Pérez-Hernández et al. 2015). Copyright
2015, ACS. e A cartoon depicting the interplay of NPs from
cell/animal imaging to therapy. Inset: TEM of Cu-doped
ZnS NPs. Reproduced with permission (Ang et al. 2016).
Copyright 2016, Wiley–VCH
Some of the recent advancements of cancer
nanomedicine include QD/Au NRs for imaging (Wu
et al. 2015), NIR‐responsive NPs for two or more
combination therapy of cancer (Duan et al. 2017),
and ultrasensitive fluorescence or magnetic based
immunoassays for detection of folic acid (Li and
Chen 2016) and C‐reaction protein in clinical
samples (Huang et al. 2018).

2.2 NPs as Drug Carriers

Although cancer nanomedicine has progressed
rapidly over the years, it elicits challenges to combat
toxicology issues (Chen et al. 2017; Shi et al. 2017;
Youn and Bae 2018). Yet again, the targeted drug
delivery is of paramount importance (Rosenblum et
al. 2018).

2.2.1 Iron Oxide NPs

The intracellular uptake of superparamagnetic iron
oxide NPs (SPIONs) is dictated by the ligands on
their surface, thus facilitating drug delivery for
cancer therapy (Huang et al. 2016; Luchini et al.
2017; Han et al. 2019). It has been found that
phospholipids such as 1,2-dimyristoyl-sn-glycero-3-
phosphocholine (DMPC) functionalized SPIONs are
easily taken up by the PC-12 cells in larger amounts,
compared to SPIONs modified with poly(ethylene
glycol) (PEG) and polyethyleneimine (PEI) (Su et al.
2017). This study has concluded that DMPC-SPIONs
can serve as potential drug carriers.
How do we suppress tumor growth? Several
methods reported in the literature to address this
issue. Once the designed NPs penetrate the tumor,
they can suppress the breast tumor growth. Iron
oxide NPs conjugated to p32 binding peptides with
the sequence (AKRGARSTA) have been
demonstrated to be most effective in treating breast
cancer in mice via better tumor homing and
penetration of the nanosystem (Sharma et al. 2017).
In another interesting work, ultrafine iron oxide NPs
(3.5 nm core size) have been shown to improve the
delivery and intratumoral distribution and retention
of NPs (Wang et al. 2017b). These small sized NPs in
comparison with their large sized counterparts were
found to be extravasated easily from the tumor
vasculature, and diffused readily into the tumor
tissue. In vivo MRI studies revealed that the ultrafine
iron oxide NPs exhibited bright T1 contrast and dark
T2 contrast in the tumor vasculature after 1 and 24 h
of intravenous administration, respectively. The
ultrafine iron oxide NPs with initial T1 contrast
aggregated into larger clusters and exhibited T2
contrast.
2.2.2 Silica-Based Carriers
Functionalized mesoporous silica-based NPs and
hollow materials emerged as transporters for
targeted drug delivery (Tang et al. 2012; Zhang et
al. 2012a; Li et al. 2017; Hai et al. 2018; Park and
Ha 2018; Kesse et al. 2019). Multifunctional
mesoporous silica NPs encompassing magnetic NPs
and an anticancer drug (camptothecin)
functionalized with TAT peptides and folic acid
grafted chitosan have been designed to enable
targeted drug delivery and MR imaging (Fig. 2.2a,
b). This nanoassembly approach showed an
enhanced anticancer effect, via the nucleus delivery
of the DNA-toxin drug, inhibiting topoisomerase I
and inducing cell apoptosis (Li et al. 2014).
Fig. 2.2 Mesoporous silica NPs for cancer therapy. a TEM
image of magnetic mesoporous silica NPs. b Cartoon
depicting the magnetic assisted delivery and camptothecin
(CPT) release into the nucleus by means of charge
conversion polymer and lysosomal escape rendered by TAT
peptides, and folic acid and citraconic anhydride grafted
chitosan. Reproduced with permission (Li et al. 2014).
Copyright 2014, Wiley–VCH. c TEM image of mesoporous
silica NP (average particle size of 87 nm). d In vivo HER2
reduction and growth inhibition of orthotopic HCC1954
tumors. Tumor growth in mice bearing orthotopic
HCC1954 tumor xenografts (n = 5/group) receiving the
same treatments as (A) but multiple doses (days of
injection are indicated by arrows). Reproduced with
permission (Ngamcherdtrakul et al. 2015). Copyright 2014,
Wiley–VCH
 Mesoporous silica NPs (core size of ~ 47–87 nm)
modified with a crosslinked cationic polymer,
polyethyleneimine–polyethylene-glycol copolymer,
(PEI–PEG) was employed for efficient delivery of
siRNA to HER2+ breast cancer (Ngamcherdtrakul et
al. 2015). Polymer coated mesoporous silica NPs
carried siRNA against the human epidermal growth
factor (h-EGF) receptor type 2 (HER2) oncogene.
This construct then coupled to anti-HER2
monoclonal antibody (trastuzumab). A scrambled
siRNA (siSCR) and a siRNA against HER2 (siHER2)
cross-linked with 10-kDa PEI, and coupled with
trastuzumab, denoted as T–siSCR–NP 10C and T–
siHER2–NP 10C, respectively (Fig. 2.2d). These
trastuzumab-targeted siRNAs carrying mesoporous
silica NPs could easily target the cancer cells that
overexpress the HER2 protein.

2.2.3 Graphene and Graphene Oxide

as Carriers
Graphene has superior qualities such as large
surface area, low toxicity, good stability, and large
drug loading capacity, and therefore proposed as a
carrier for improved delivery of anticancer drug,
doxorubicin (DOX) (Wang et al. 2014; Orecchioni et
al. 2015). Graphene integrated with fluorescent QDs
can act as reporters to monitor the drug delivery. To
achieve specific targeting, a transferrin ligand (Trf)
attached to the surface of the graphene sheet (Chen
et al. 2013b).
 Graphene oxide can act not only as a drug
delivery vehicle but also as a substrate for the
attachment of nanocrystals (Zhang et al. 2010; Zhou
et al. 2014b). Very recently, we have reported the
grafting of ZnS:Mn doped nanocrystal and
anticancer drug onto graphene oxide for cancer cells
labelling (Fig. 2.3) (Dinda et al. 2016). High drug
entrapment efficiency, slow drug release, better
cancer cell labelling and killing efficiency are the
traits of this novel system. This demands further
work for in-vivo animal imaging and targeted drug
delivery. Besides, carbon nanodots have been
exploited for the delivery of another anticancer drug,
paclitaxel (PTX) (Gomez et al. 2018).

Fig. 2.3 Grafting of ZnS:Mn doped nanocrystal and

anticancer drug onto graphene oxide for delivery and cell
labelling. Reproduced with permission (Dinda et al. 2016).
Copyright 2016, Wiley–VCH
2.2.4 Peptide/Polymer Mediated
Delivery
The efficient delivery of anticancer drugs (i.e.,
therapeutic efficacy) is an important goal in cancer
nanomedicine. Towards this goal, an intra-nuclear
drug delivery approach using dexamethasone-
conjugated micelle has been developed (Wang et al.
2017a). Cell and tumor penetrating peptides have
been designed for improved drug delivery (Ruoslahti
2017). Our group has developed QD-peptide
bioconjugates for nuclear targeting of human
mesenchymal stem cells (hMSCs) (Narayanan et al.
2013). To avoid the intracellular degradation of
drugs in lysosomes and poor delivery to the nucleus,
drugs can be encapsulated in copolymer micelles
that are composed of N-(2-hydroxypropyl)
methacrylamide (HPMA) (Zhou et al. 2017). The
HA2 membrane fusion peptide grafted onto HPMA
copolymers disrupted lysosome membranes. This
work also illustrated that the micelles containing
nucleus-targeting retinoic acid and the drug cargo
(H1 peptide), efficiently evaded the lysosomes and
targeted the nucleus of MCF-7 breast cancer cells,
and further inhibited the tumor growth in mice.
Oligonucleotides possessing high immune-
stimulatory activity such as cytosine-phosphate-
guanine (CpG) conjugated to bifunctional NPs
encompassing MnO2–AgNCs–DOX conjugate can be
used for enhanced cancer immunotherapy (Wang et
al. 2017c). Here, MnO2 sheets acted as unique
support for the integration of chemotherapy drug
DOX and the immunotherapeutic agent CpG-AgNCs.
Furthermore, transport of NPs and drug mediated by
DNA enabled endosomal escape and intracellular
delivery (Muro 2014). A γ-glutamyl transpeptidase-
responsive camptothecin–polymer conjugate for
efficient suppression of solid tumors has been
developed (Zhou et al. 2019). This conjugate also
prolonged the survival of pancreatic tumour-bearing
mice, compared to the chemotherapeutic drug
gemcitabine.

2.2.5 Liposomes for Targeted

Delivery
Liposomes are one of the emerging nanoscale drug
delivery systems (Torchilin 2014; Zhao and Feng
2015; Vahed et al. 2017). They offer benefits such as
low clearance rate, and improved targeting abilities.
The potential target for siRNA-based cancer
treatment is Bmi1 gene, which is overexpressed in
various human tumors. Although siRNA-based
therapy has potential merits in cancer treatment, it
suffers from limited delivery targeting Bmi1 gene,
low bioavailability and reduced efficacy. Liposome
assisted co-delivery of folate-doxorubicin, and Bmi1
siRNA showed advantages in inhibiting the tumor
growth via silencing the expression of Bmi1 gene
and high targeting efficiency by folate receptor
(Yang et al. 2014). Studies have shown that the
anticancer drug, DOX did not respond to M109 lung
tumors. However, a nanoassembly comprising of
DOX with squalene, a natural lipid precursor for the
biosynthesis of cholesterol, dramatically improved
the anticancer efficacy, inhibiting the tumor by 90%
(Maksimenko et al. 2014). This squalene-DOX
nanomedicine reduced the cardiac toxicity induced
by the drug and hence improved the therapeutic
index of the drug.
PEGylated liposomal doxorubicin (PLD) is the first
FDA-approved nanomedicine (Bobo et al. 2016) for
cancer therapy of breast, ovarian, multiple myeloma,
and Kaposi sarcoma (Gabizon et al. 2016). However,
PLD has not replaced the conventional doxorubicin
for the treatment of breast cancer, and its clinical
application is not widespread. By exploiting the
selective biodistribution and homing potential of PLD
to tumors, and pharmaceutical nanotechnology with
advanced theranostic platforms, will have great
impact on future clinical applications.

2.3 Photothermal Therapy

Photothermal therapy (PTT) utilizes the NPs that can
generate heat upon laser irradiation to induce
apoptosis of cancer cells (Melamed et al. 2015). A
wide variety of plasmonic materials such as Au, Ag,
Cu, CuSe, graphene, carbon nanotubes have been
exploited for photothermal cancer therapy. These
plasmonic nanomaterials exhibit heat upon
excitation to NIR light and less absorption by
biological tissues.
Metallic nanostructures such as gold nanorods
(Au-NRs) (Zhou et al. 2014a; Chen et al. 2013a), Au
nanocages (Yavuz et al. 2009), Au–Cu alloy
nanocrystals (He et al. 2014; Xia et al. 2017) exhibit
absorption in the near-infrared (ca. 800–1200 nm)
that allows for the excitation at this wavelength,
thereby enabling photothermal effects, and
photothermal therapy of cancer. Due to their large
absorption cross sections in NIR region, Au-NRs
(Zhang et al. 2012b), Au-prisms (Pérez-Hernández et
al. 2014; Pelaz et al. 2012), Au-cages (Yavuz et al.
2009) and Au-nanostars (Yuan et al. 2012; Liu et al.
2015b; Liu et al. 2017b) have shown great potentials
in photothermal therapy of cancer. All these Au-NRs,
Au-prisms and Au-cages can act as nanoheaters
under NIR illumination, exhibiting promising
photothermal application in nanomedicine. Besides
Au nanostructures, bismuth sulfide nanorods (Liu et
al. 2015a), and Te-NRs (decorated by
polysaccharide–protein complex) (Huang et al. 2017)
have been used for combined chemo and
photothermal therapy.
Recent work has demonstrated the photothermal
therapy of PTW-Te-NRs (PTW: extracted from
Pleurotus tuber-reguim) (Huang et al. 2017). The
effects of Te-NPs and PTW-Te-NRs on HepG2 cells
after laser irradiation for different time intervals
captured by IR camera indicated a sharp rise in
temperature with the maximum of 68.2 °C (Fig. 2.4a,
b). The fact that the reduction in cell number and
rounded cell shape for both Te-NPs and PTW-TeNRs
with laser treated cells clearly indicated the
apoptosis of cancer cells (Fig. 2.4c). The
fluorescence staining (live and dead cell assays) with
calcein acetoxymethyl (green) and propidium iodide
(red) further supported the above observation
(Fig. 2.4d). This study demonstrated the potential of
these Te-NRs for chemo-photothermal combination
therapy of cancer (Fig. 2.4e).

Fig. 2.4 Tellurium nanorods (Te-NRs) for PTT. a IR

camera captured thermal images of HepG2 cells incubated
with either Te-NPs or PTW-Te-NRs with specified
concentrations upon NIR light irradiation for 5 min. b
Temperature profiles of NPs and NRs (20 mg L−1) exposed
HepG2 cells recorded at 1, 3 and 5 min of irradiation
(808 nm, 3 W cm−2). c Bright-field images of HepG2 cells
with control groups (PBS, laser only, free TeNPs, free PTW
− TeNRs) and laser irradiated cells (TeNPs + Laser, and
PTW − TeNRs + Laser). d Fluorescence images of HepG2
cells treated with TeNPs or PTW-TeNRs, and stained with
calcein AM (green) and PI (red). e In vivo photothermal
therapy (PTT) and MRI of TeNRs (PTW − TeNRs + Laser)
treated mice after 21 days of observation. Reproduced with
permission (Huang et al. 2017). Copyright 2017, Wiley–
VCH
Other potential NP systems are plasmonic
bimetallic Au–Cu nanocrystals for combined chemo
and PTT (He et al. 2014; Nanda et al. 2019), core–
shell Au–Se nanocomposites for radio- and chemo-
therapy (Chang et al. 2017), and targeted
combination therapy of cancer using NIR dye (ICG:
indocyanine green)—bovine serum albumin
nanocomplex as photothermal agent and DOX as
chemotherapy drug, co-encapsulated into
engineered red blood cells (RBCs) carriers (Sun et
al. 2015). In the later system, RBCs heated up due to
NIR irradiation, resulting in a burst drug release (ca.
80%) within 5 min.
In conclusion, cancer nanomedicine shows
promises in early diagnostics and preoperative
therapeutics, neoadjuvant radiotherapy,
chemotherapy, phototherapy, and immunotherapy
(Qu et al. 2023).

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© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2023
S. Tamil Selvan, Nanomedicine, Nanotheranostics
https://doi.org/10.1007/978-981-99-2139-3_3

3. Nanomedicine for
Neurodegenerative Diseases
Subramanian Tamil Selvan 1
(1) Alpha Biomedical Pte. Ltd., Singapore,
Singapore

Subramanian Tamil Selvan

Email: [email protected]

Abstract
This chapter deals with the design of organic NPs
(e.g., curcumin, green tea polyphenol—EGCG), and
inorganic NPs (e.g., Au, ZnO, CeO2) in decreasing or
inhibiting the amyloid aggregation and tau
hyperphosphorylation associated with the
Alzheimer’s disease (AD). Different NP-based drug
delivery approaches (e.g., apolipoprotein, peptides,
dendrimers) to the delivery of CNS drugs across the
blood–brain barrier (BBB) are discussed.

Keywords Ceria nanoparticles – ROS scavengers –

Nanomedicine – Targeted delivery – Diagnostics –
Neurodegenerative diseases – Alzheimer’s disease –
Parkinson’s disease – Biosensors
The most common neurodegenerative diseases are
Alzheimer’s disease (AD) and Parkinson’s disease
(PD). Other common neurological disorders are
acute spinal cord injury, epilepsy and seizures,
migraines, multiple sclerosis, brain tumors, and
stroke. Some of these degenerative nerve diseases
are genetic, and they affect the activities of our body
such as balance, movement, talking, breathing, and
heart function. The main causes of the above
neurodegenerative diseases are mostly unknown;
however, it could originate from a medical condition
(e.g., stroke, tumor or alcoholism), or toxins, and
viruses. Importantly, although brain, spinal cord, and
nerves (central nervous system, CNS) are
safeguarded by the meninges, serious bacterial,
viral, or fungal infection in the brain can cause life-
threatening diseases such as meningitis.
It is highly indispensable that the CNS drugs
should pass through the blood–brain barrier (BBB).
Engineered nanostructures and nanomaterials hold
great promise for both diagnosis and therapeutic
applications. They can also be useful for combating
microbial drug resistance, due to their high surface
area and innate antibacterial activity. Several
nanoparticle-based approaches have been delineated
to enhance the CNS delivery of drugs across BBB
(Tamil Selvan et al. 2020).
In the United States itself, over 6.2 million people
suffered from AD in 2022, according to a report from
the Alzheimer’s Disease Association.
Neurodegenerative AD correlates closely to the
aggregation of amyloid beta (Aβ) proteins and hyper-
phosphorylated tau protein, neurofibrillary tangles
(NFTs). However, the amyloid aggregation is the
early event in AD, and its progression (memory
cognitive impairment, MCI) is associated to the tau
NFTs.
Importantly, nanomaterials pave their way to
combat the protein amyloid aggregation (Wang et al.
2017). For instance, maghemite iron oxide NPs
coated with dextran polymer inhibited the amyloid
fibrillogenesis of human insulin (Lu et al. 2018).
Nanomedicine for neurodegenerative diseases has
been emerging with an aim to ameliorate the
neuroprotection and combat the difficulties
associated with the passage of neuro-protecting
agents through the blood–brain-barrier (BBB).
Recently, different nano-based systems for
enhancing the neuroprotective efficacy have been
developed. In a recent review, we have discussed the
effects of coordination ligands on the surface of
organic NPs such as flavonoids (e.g., curcumin,
green tea polyphenol—EGCG,), and inorganic NPs
(e.g., Au, ZnO, CeO2) in decreasing or inhibiting the
amyloid aggregation and tau hyperphosphorylation
(Fig. 3.1) (Tamil Selvan et al. 2021).
Fig. 3.1 The interplay of ligands in the design of tracers
for imaging, and organic/inorganic NPs for therapeutic
applications of AD. Reproduced with permission (Tamil
Selvan et al. 2021) Copyright 2021, Elsevier

3.1 Design of NPs for Inhibiting

Protein Aggregation
The new term “nano-neuroscience” is an emerging
paradigm, which bridges two burgeoning fields of
nano- and neuro-science (Kumar, Tan et al. 2017).
The probe development with the advent of
nanotechnology opens up new avenues for
diagnosing and treating neurodegenerative diseases.
Nanostructures with binding ability to aggregated
Aβ proteins and permeability to the BBB are useful
nanomedicine platforms (Goldsmith et al. 2014;
Huang et al. 2015; Aparicio-Blanco et al. 2016).

3.1.1 Au NPs
Several NP-based strategies have been designed to
prevent the tau protein hyper-phosphorylation, so
that apoptosis and neurodegeneration can be
inhibited. The anthocyanin-loaded PEG-Au NPs
prevented the hyper-phosphorylation of tau protein,
thereby enhancing the neuroprotection in an Aβ1–42
mouse model of Alzheimer’s disease (AD) (Ali et al.
2017). This is considered as one of the promising
nanomedicine strategies in preventing
neurodegenerative diseases. Another study
suggested that anthocyanins act as effective anti-
oxidant neuroprotective agent in combating
oxidative stress, thus improving memory
impairments (Ali et al. 2018). Such Au NPs are good
candidate systems for traversing the BBB to probe
the brain-tumor surgery (Gao et al. 2017).
Conjugation of two peptide inhibitors (VVIA and
LPFFD) onto Au-NPs reduced the cytotoxicity caused
by Aβ aggregation (Xiong et al. 2017). Jana and co-
workers have found that water-soluble curcumin-
functionalized Au-NPs (Au-curcumin) could inhibit
amyloid fibrillation and disintegrate or dissolve
amyloid fibrils. This is a promising therapeutic
approach to the neurodegenerative diseases (Palmal
et al. 2014). In vitro inhibition of Aβ peptide
aggregation into fibrils by noble metal Au and Pt
NPs indicated clearly their binding affinity to
amyloids (Streich et al. 2016).

3.1.2 Ceria NPs

Cerium oxide or ceria (CeO2) NPs emerge as an
effective antioxidant for various neurodegenerative
diseases including Alzheimer’s and Parkinson’s
diseases, ischemic stroke, and multiple sclerosis
(Naz et al. 2017). Surface-functionalized ceria NPs
have mitigated the mitochondrial oxidative stress
and suppressed tau hyper-phosphorylation (Chen et
al. 2018). The nanocomposite was fabricated by
assembling ceria (CeNC) and iron oxide nanocrystals
(IONC) onto mesoporous silica NPs. The addition of
preformed NOTA-T807 (NOTA: 1,4,7-
triazacyclononane-1,4,7-triacetic acid; T807: tau PET
tracer) and methylene blue (MB) completed the
formation of multifunctional (CeNC/IONC/MSN-
T807-MB) nanocomposite. The nanocomposite
labelled with 68Ga and NOTA-T807 allowed for active
targeting and imaging of hyper-phosphorylated tau
by PET and MRI, and combinational therapy of ROS
scavenging and MB release (Fig. 3.2). This work
sheds light in preventing mitochondrial oxidative
stress induced hyper-phosphorylation of tau (Chen et
al. 2018).
Fig. 3.2 Ceria NPs for the scavenging of ROS in mitigating
oxidative stress in AD. Design of multifunctional NPs
(CeNC/IONC/MSN-T807-MB) for targeting hyper-
phosphorylated tau and combinational therapy of ROS
scavenging and methylene blue release. Reproduced with
permission (Chen et al. 2018). Copyright 2018, ACS
In another interesting work, ceria NPs were
employed for scavenging intra- and extra-cellular
and mitochondrial ROS in PD model mice (Fig. 3.3)
(Kwon et al. 2018). The ability of ceria NPs in
scavenging ROS redox reactions (switching between
Ce3+ and Ce4+ ions) is based on the enzymatic (SOD
and catalase) mimetic activity (Fig. 3.3A). However,
the cell uptake is dependent on the particle size,
surface coating and charge. Ceria NPs possessing
negative charge labelled SH‐SY5Y cells cytoplasm,
but those coated with triphenylphosphonium (TPP)
and PEG labelled the mitochondria, as inferred from
confocal images (Fig. 3.3B).
Fig. 3.3 A Schematic illustration of ceria NP in ROS
scavenging reactions based on the antioxidant enzymes—
super oxide dismutase (SOD) and catalase. B Confocal
images of SH‐SY5Y cells labelled with ceria NPs (blue:
lysosomes; red: mitochondria, green: FITC‐conjugated
NPs). Scale bars are 10 μm. C Tyrosine hydroxylase (TH)
expression in the control and MPTP‐induced PD mice
brains: (a) immunohistochemistry (IHC) images; (b) IHC-
fluorescence (IHF) images; (c) Confocal images showing
the distributions of ceria NPs in each group. Scale bars:
1 mm. MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Reproduced with permission (Kwon et al. 2018). Copyright
2018, Wiley–VCH
Immunohistochemistry (IHC) and fluorescence of
the brain sections visualized the distribution of
tyrosine hydroxylase (TH) and showed higher levels
in in the striatal regions of the PD for ceria NP-
treated groups (Fig. 3.3C). This work demonstrated
the usefulness of ceria NPs in inhibiting the
microglial activation and lipid peroxidation via the
scavenging of intracellular or mitochondrial ROS,
and in protecting the tyrosine hydroxylase in the
striatal of regions of the PD mice.
Importantly, ceria NPs showed excellent
antioxidant properties to combat reactive oxygen
species (ROS) induced oxidative stress by targeting
mitochondria in AD (Kwon et al. 2016), protection
against ischemic stroke (Kim et al. 2012), and for
selective scavenging of mitochondrial ROS in
Parkinson’s disease (Kwon et al. 2018).
Furthermore, bimodal ceria/magnetite (Kim et al.
2019), and Ce/MnMoS4 (Guan et al. 2016) core–shell
NPs have been developed for addressing multiple
facets of AD. Conversely, ceria NPs served as
neuroprotection agents (Rzigalinski et al. 2017), and
used to ameliorate the neurochemical impairments
(induced by hydroxydopamine) in PD rats (Hegazy et
al. 2017).
3.2 NP-Based Drug Delivery Carriers
The delivery of drugs to the central nervous system
(CNS) is highly indispensable and a key challenge in
the development of drugs (Dong 2018; Terstappen et
al. 2021). Several technologies have been developed
to deliver therapeutics or biopharmaceuticals such
as monoclonal antibodies to the CNS, some of which
have entered clinical trials. To achieve the best and
sufficient delivery of drugs across the brain, all
physiological barriers (e.g., cellular uptake barrier,
BBB, endosomal/lysosomal barrier, and controlled
drug release) have to be overcome (Banks 2016;
Arvanitis et al. 2020). Different NP based designs for
overcoming the above biological barriers to drug
delivery has been delineated earlier (Blanco et al.
2015).
Drug delivery vectors such as polymeric NPs,
lipid-based NPs, inorganic NPs, extracellular
vesicles, and exosomes have been widely developed
for the delivery of nucleic acid drugs to the brain
(Blanco et al. 2015; Lu et al. 2023). A shuttle
peptide, Angiopep-2 that can cross the BBB, has
been found to improve the delivery of gold nanorods
(Au-NRs) functionalized with PEG to the brain
parenchyma (Velasco-Aguirre et al. 2017).
Mesoporous silica NPs were also used as carriers
for the co-delivery of plasmid DNA and siRNA for
enhancing the generation of dopaminergic neurons
from induced pluripotent stem cells (iPSCs) (Chang
et al. 2017). Mesoporous silica NPs loaded with
ultrasmall cerium oxide have been used as an ROS-
responsive and -scavenging nanomedicine for the
application of targeted drug delivery system
combined with antioxidant therapy (Purikova et al.
2022).

3.2.1 Apolipoprotein
Nanostructured lipid carriers have been widely
employed as carriers for different neurodegenerative
disorders such as Alzheimer’s disease, Parkinson’s
disease, brain cancer, ischemic stroke, and multiple
sclerosis (Tapeinos et al. 2017). High-density
lipoproteins have been regarded as nature’s
multifunctional NPs, opening new avenues in drug
delivery strategies (Kuai et al. 2016). High-density
apolipoprotein (ApoE3-rHDL)-based nanostructures
have been designed to bind to Aβ monomers and
oligomers with high affinity and degrade them by
glial and liver cells (Song et al. 2014). The in vivo AD
animal model study showed the attenuated amyloid
deposition and microgliosis, and revival of memory
loss.

3.2.2 Dendrimers, Peptides, and

Inorganic NPs
Dendrimers have been explored as powerful building
blocks of nanomaterials for crossing BBB and
neuronal cells uptake in the CNS disease (Leiro et al.
2018; Santos et al. 2018). Phosphorus dendrimers
have been regarded as drugs for neurodegenerative
diseases (Caminade 2017). Polymer NPs such as N-
isopropylacrylamide: N-tert-butylacrylamide
(NiPAM:BAM) showed both drug delivery capability
and anti-amyloid properties (Cabaleiro-Lago et al.
2009; Shcharbin et al. 2017).
Finally, nanotechnology enables for traversing the
BBB, thereby allowing brain cancer theranostics
(Tang et al. 2019). Some of the other notable
findings include benzylamide based anti-
inflammatory drug conjugates for CNS delivery
(Eden et al. 2019), peptide mediated brain delivery
of NPs (McCully et al. 2018), AuNR–peptide–siRNA
complex (Vio et al. 2018), fluorescent carbon dots
for the targeting of brain cancer cells (Zheng et al.
2015), biodegradable Cu2–xSe NPs for monitoring
BBB (Zhang et al. 2018), and stapled RGD peptide
for glioma-targeted drug delivery (Ruan et al. 2017).
In a recent interesting work, a lipoprotein-
inspired nanoscavenger has been designed to
attenuate the inflammatory dysfunction of microglia
resulting from excess amyloid-β peptide (Aβ) in
Alzheimer’s disease (AD) (Zhang et al. 2022). The
design consisted of a phosphatidic acid-
functionalized high-density lipoprotein (pHDL),
curcumin, and β-site APP cleavage enzyme 1
targeted siRNA (siBACE1) to modulate microglial
dysfunction, by mimicking the natural lipoprotein
transport pathway (Fig. 3.4).
Fig. 3.4 Schematic illustration of lipoprotein-inspired
nanoscavenger for modulation of neuroinflammation in
Alzheimer’s Disease (AD) therapy (Zhang et al. 2022).
Copyright 2022 ACS
The benefits of this strategy include promoted Aβ
clearance (via the pHDL penetration of BBB and
sequential targeting of Aβ plaque, an antibody-like
Aβ binding affinity), a normalized microglial
dysfunction (through blocking of the NF-κB
pathway), and reduced Aβ production (via gene
silencing, 44%). This method enabled for the
reversal of the memory deficit and
neuroinflammation in treated mice.

3.3 NP-Based Biosensors for AD

Diagnosis
Although therapeutic strategies are important, it is
more important to diagnose the AD patients in an
early stage using biomarkers (Amen et al. 2022; Oh
et al. 2022; Zheng et al. 2023). However, it is a
challenge to detect AD blood protein biomarkers
owing to a low abundance of biomarkers in a
complex serum environment. To obviate these
difficulties, recently a nanomaterial-based
semiconducting carbon nanotube (CNT) field-effect
transistor (FET) biosensor has been designed (Chen
et al. 2022). First, thin films of CNT were mass
produced and combined with oligonucleotide
aptamers to achieve highly sensitive and selective
detection of the AD human serum biomarkers of
Aβ42 and Aβ40 peptides in sub-femtomolar detection
range. The benefits of this approach include the
selectivity ratios of up to 730–800% (for Aβ40 and
Aβ42), rapid response time (within several minutes),
a large dynamic range (> 104), and low-cost point of
care diagnostic test (Fig. 3.5).
Fig. 3.5 Schematic illustration of a carbon nanotube
(CNT) field-effect transistor (FET) biosensor for the
selective detection of the AD human serum biomarkers of
Aβ42 and Aβ40 peptides in sub-femtomolar detection range
(Chen et al. 2022). Copyright 2022, ACS
Some of the recent advancement in early
diagnosis of AD biomarkers include electrochemical
aptasensor based on Y probe for the specific
molecular recognition of β-amyloid oligomer (Zheng
et al. 2023), and several nanotechnology-mediated
approaches for both AD and dementia diagnostics
and therapy (Leszek et al. 2017; Hettiarachchi et al.
2019; Kumari et al. 2023; Shao et al. 2023).
In conclusion, we have provided a comprehensive
overview of the recent developments of
nanomedicine assisted strategies (e.g.,
organic/inorganic NP-based diagnostics and protein-
based drug delivery) for inhibiting the amyloid
aggregation and tau hyperphosphorylation
associated with the Alzheimer’s disease (AD), and
carbon nanotube-based biosensor strategies for
selective detection of the AD human serum
biomarkers.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2023
S. Tamil Selvan, Nanomedicine, Nanotheranostics
https://doi.org/10.1007/978-981-99-2139-3_4

4. Nanomedicine for
Orthopaedics
Subramanian Tamil Selvan 1
(1) Alpha Biomedical Pte. Ltd., Singapore,
Singapore

Subramanian Tamil Selvan

Email: [email protected]

Abstract
This chapter discusses the usefulness of different
nanocomposites for the promotion of angiogenesis,
osteogenesis, and bone regeneration. Typical
examples include graphene oxide–collagen
nanocomposite, polylactic acid (PLA)—carbon
nanotubes, dexamethasone-loaded calcium
phosphate—collagen nanocomposites, nanofiber
scaffolds (e.g., chitosan/poly-ethylene oxide), porous
hydroxyapatite (HA) and reduced graphene oxide
(rGO) nanocomposite scaffold, and injectable bone
cement reinforced with Au NPs decorated HA/rGO
nanocomposites for bone regeneration.
Keywords Nanomedicine – Bone regeneration –
Graphene oxide/collagen nanocomposite –
Chitosan/poly-ethylene oxide scaffolds – Porous
hydroxyapatite/graphene oxide scaffolds – Hydrogel
scaffolds – Tissue engineering – Orthopaedics

Nanomedicine and tissue engineering approaches

have manifested great promise in orthopaedic
trauma, including high bacterial infection risk, low
bony reconstruction and bone-healing (Behzadi et al.
2017). The emergence of novel nanocomposite
materials provide great platforms in addressing
these issues by exhibiting not only antibacterial
properties, but also offer mechanical, biochemical,
physicochemical properties, and facilitate
osteogenesis/angiogenesis necessary to accelerate
the healing process in bone regeneration (Sullivan et
al. 2014).

4.1 Nanoscale Materials for Bone

Tissue Regeneration
Nanoscale materials such as hydroxyapatite (HA)
and calcium phosphate NPs can integrate easily with
the bone since they are the main constituent of the
natural bone. β-tricalcium phosphate (β-TCP) has
both osteo-conductive, osteo-inductive, and cell-
mediated resorption properties that promotes the
new bone formation due to its excellent
biodegradability (degradation into calcium and
phosphate ions) in the body (Park et al. 2018).
4.1.1 Natural Polymers Based
Scaffolds for Bone Regeneration
Several β-TCP based scaffolds combined with natural
polymers, such as chitosan/gelatin (Serra et al.
2015), and dextran (Ghaffari et al. 2020), and
interconnected porous scaffolds (Wang et al. 2019a,
b) have been demonstrated to be useful for bone
tissue regeneration. These scaffolds promoted cell
migration, proliferation, and angiogenesis. Similarly,
β-TCP based scaffolds combined with graphene oxide
(GO) nanoparticles showed great potential in bone
tissue engineering (Liu et al. 2020).
Studies have demonstrated the applications of
nanocomposites such as polylactic acid (PLA)—
carbon nanotubes for enhanced osteoblast adhesion
and proliferation (Mazaheri et al. 2015),
dexamethasone-loaded calcium phosphate—collagen
nanocomposites for the promotion of angiogenesis
and osteogenesis (Chen et al. 2018), and nanofiber
scaffolds (e.g. chitosan/poly-ethylene oxide) for bone
regeneration (Christenson et al. 2007).
Although hydrogels such as type I collagen (COL)
has active role in bone tissue repair, it suffers from
poor mechanical strength. Addition of graphene
oxide (GO) nanosheets greatly enhance the
mechanical strength. This has been recently
demonstrated in curing the cranial defects in rats by
incorporating GO-COL into cultured osteo-
differentiated (OiECM) bone marrow mesenchymal
stem cells (BMSCs) (Fig. 4.1) (Liu et al. 2018). This
approach ameliorated the osteogenic ability,
mechanical strength, and biocompatibility of the GO-
COL hydrogels. In another recent study, mesoporous
silica bioactive glass—graphene oxide scaffold
demonstrated its potential in promoting vascular
ingrowth, thereby repairing bone defects in a rat
cranial model (Wang et al. 2019a, b).

Fig. 4.1 Application of graphene oxide–collagen-I

nanocomposite along with osteo-inductive ECM in curing
the cranial defect in rat. Reproduced with permission (Liu
et al. 2018). Copyright 2018, ACS

4.1.2 Hydroxyapatite and Graphene

Oxide Scaffolds for Bone
Regeneration
Three-dimensional porous hydroxyapatite and
reduced graphene oxide HA/rGO scaffolds with
ordered pore structure enabled beneficial cell
adhesion and ingrowth, promoting the osteogenic
differentiation of BMSCs (Fig. 4.2) (Zhou et al.
2019). The HA/rGO-6/0.3 scaffolds did not show
cytotoxicity, but promoted the cell proliferation of
BMSCs. This study also confirmed that newly formed
bones filled inside the scaffold. With many new bone
formations, the scaffold cracked slowly and exposed
rGO for further proliferation of stem cells. Finally,
the cracked scaffold degraded and wrapped by the
new bone. These implants accelerated bone
ingrowth and repair of fractured sites. In another
interesting work, injectable bone cement was
reinforced with Au NPs decorated HA/rGO
nanocomposites to strengthen bone regeneration
(Chopra et al. 2023).

Fig. 4.2 Flow-chart representation of the application of

porous scaffold made of hydroxyapatite and reduced
graphene oxide nanocomposite for bone ingrowth and
repair. Reproduced with permission (Zhou et al. 2019).
Copyright 2019, ACS
Other recent work for bone regeneration and anti-
infection demonstrated the preparation of nano-HA
scaffold loaded with glycopeptide antibiotics (e.g.,
vancomycin) and its sustained release from the
composite polylactic acid (PLA) and poly (lactic acid-
glycolic acid) scaffold microspheres (Li et al. 2023).
These scaffolds showed excellent biomechanical and
biocompatible properties, thereby effectively
inhibiting the growth of Staphylococcus aureus, and
repairing bone defects.

4.1.3 Antibacterial Nanoparticles

Coated Orthopaedic Implants
In orthopaedic implants, NPs have been used
especially as coating materials to combat bacterial
infections. The drug resistant bacterial infections
(e.g., Methicillin-resistant Staphylococcus aureus,
Staphylococcus epidermidis) are serious in traumatic
injury patients who stay longer in intensive care
units. The selenium (Se) NP (with the size of 30–
70 nm) coatings on titanium implants strongly
inhibited the biofilm formation, caused by the
aforementioned drug resistant bacteria in an
infected femur model rats (Tran et al. 2019).
Chitosan scaffolds with Ag or Se NPs served
effectively as antibacterial implants for wound
dressing application (Biswas et al. 2018). Although
both Ag and Se NPs showed their antibacterial
effects to three bacterial strains (S. aureus, MRSA
and E. coli), Ag caused cytotoxicity to mouse
fibroblast cells, whereas Se NPs did not. Conversely,
Au-NPs owing to their anti-inflammatory property,
exhibited promising therapeutic effects to
iontophoresis, which is a therapeutic treatment of
injury. The Au-NPs enhanced the effect of a
nonsteroidal anti-inflammatory drug, diclofenac
diethylammonium, while reducing inflammatory
cytokines in treating traumatic Achilles tendinitis
(Dohnert et al. 2012). These three combinations (Au-
NP, drug, iontophoresis) lowered the levels of
inflammatory cytokines in treated rats, compared to
untreated control groups.
The focal skeletal malignant osteolysis is another
serious problem. Polymer based NPs such as
polylactide formulations loaded with DOX, coated
with bone-seeking pamidronate, have been used for
the targeted therapy of malignant skeletal tumors
(Yin et al. 2016). This nanoformulation attenuated
the focal skeletal malignant osteolysis progression in
a murine model, compared to the control, non-
targeted DOX-NPs.

4.2 Hydrogel Scaffolds for Osteogenic

Differentiation of Stem Cells
Novel zwitterionic Chitosan/β-tricalcium phosphate
hydrogel/GO scaffolds have also been used for bone
tissue engineering (Wang et al. 2023). These
scaffolds displayed improved osteogenic
differentiation of bone mesenchymal stem cells
(Fig. 4.3). The porosity of these scaffolds reported to
be increased with an increase in GO concentration.
Both swelling and degradation percentage of the
scaffolds decreased with increasing GO
concentration.

Fig. 4.3 a Optical images of different hydrogels. Z-CS/β-

CTP: Zwitterionic Chitosan/β-tricalcium phosphate; GO:
graphene oxide. The color gets intensified with an increase
of GO (GO-1 to GO-4). b Porosity of corresponding scaffolds
as in (a) increased with an increase in GO concentration. c
SEM images of those scaffolds with different GO
concentrations. Lower panels are enlarged images of those
red dotted boxes in the upper panels. d Swelling
percentage and e Degradation percentage of scaffolds with
different GO concentrations (Wang et al. 2023)
Alternatively, calcium silicate (CS) bioceramics
has attracted a great deal of attention, owing to their
excellent capability to stimulate osteogenesis (Zhou
et al. 2021). This work has demonstrated a
significant enhancement of the osteogenic
differentiation of bone marrow mesenchymal stem
cells (BMSCs) via the stimulation of a macrophage
conditioned medium pre-treated with CS extracts.
Compared to β-TCP implants, CS scaffolds promoted
the osteogenesis due to the presence of oncostatin-M
(OSM) protein in the macrophage-conditioned
medium, thereby accelerating the new bone
formation at defective sites in the femoral bone
defects in rats. Micro-CT 3D reconstruction images,
and the percentage calculation of bone mineral
density (BMD), and bone volume relative to its total
tissue volume (BV/TV) confirmed the superiority of
CS scaffolds implants over β-TCP implants (Fig. 4.4).
Fig. 4.4 a Micro-CT 3D reconstruction (coronal section) of
bone regeneration in the femoral bone defect in animals;
white, yellow, and blue refer to the original bone, new
bone, and implanted material, respectively. b Bone mineral
density (BMD) versus time in weeks. c Percentage of new
bone formation, relative to its total tissue volume (BV/TV)
(n = 10 rats/batch) (Zhou et al. 2021)

4.2.1 Polymer/Stem Cells Implanted

Hydrogels for Cartilage Regeneration
Very recently, an innovative articular cartilage
(ARTiCAR) implant combining nanofibrous poly-ε-
caprolactone (PCL) and BMSCs in
alginate/hyaluronic acid hydrogel has been reported
for osteoarticular regeneration (OAR) (Keller et al.
2019). The preclinical safety evaluation of the
NanoM1-BMP2 bone wound dressing implant in vitro
and BMSCs mixed in alginate/hyaluronic acid
hydrogel in vivo have been carried out for
subchondral bone and cartilage regeneration
(Fig. 4.5).
Fig. 4.5 a Scheme depicting the combined advanced
therapy medicinal product (ATMP) ARTiCAR (ARTicular
CArtilage and subchondRal bone implant) involving
subchondral bone (compartment 1) and articular cartilage
(compartment 2) regenerations. The composite combines
an FDA-approved synthetic polymer poly-ε-caprolactone
(PCL) and bone marrow-derived mesenchymal stem cells
(BMSCs) embedded in alginate/hyaluronic acid hydrogel.
The NanoM1-BMP2 refers to the nanofibrous PCL
functionalized with bone morphogenetic protein 2 and
tested for in vitro cytotoxicity (step 1). The whole ARTiCAR
tested for in vivo toxicity, biodistribution studies in an
osteochondral defect nude rat model (step 2) and for
feasibility, non-invasive monitoring (step 3) in a sheep
intra-articular model. b Cartoon depicting the usefulness of
The ARTiCAR for simultaneous regeneration of the
articular cartilage and the subchondral bone. In the first
step, the NanoM1-BMP2 is applied to the injured
subchondral bone. In the second step, the harvested
BMSCs from the patient is mixed with the hydrogel and
applied to fill the osteoarticular defect. Reproduced with
permission (Keller et al. 2019). Copyright 2019, Nature
Publishing Group

4.3 Nanomedicine for Controlled

Orthopaedic Drug Delivery
To avoid the complications such as infections
associated with post-operative orthopaedic surgery,
nanomedicine based controlled drug delivery of
antibiotics would be beneficial. Plant based
polysaccharides have emerged as potential
candidate systems for orthopaedic drug delivery and
treatment (Hormozi 2023).
Three-dimensional (3D) printing technology is a
powerful technique for the preparation of tissue
engineering scaffolds (Adarkwa et al. 2023; Mo et al.
2023; Samie et al. 2023; Song et al. 2023). For
instance, polylactic acid (PLA)/nano-hydroxyapatite
(nHA) scaffolds (with high porosity and
interconnected 3D networks) were loaded with
vancomycin (Van)-based chitosan (CS) hydrogel (CS-
Van). The resulting PLA/nHA/CS-Van composite
scaffold showed enhanced mechanical and
biocompatible properties, hydrophilicity, sustained
release of the drug in vitro (> 8 weeks).
Furthermore, the composite scaffold inhibited the
growth of Staphylococcus aureus (S. aureus)
effectively, demonstrating its efficacy for treating
infected bone defects (Fig. 4.6) (Gao et al. 2023).
Fig. 4.6 a SEM images of CS-Van, b the standard curve of
Van, c In vitro release profiles of CS-Van, S3 and S4, d
antibacterial test, e inhibition zone diameter for S. aureus
with (a) PLA/nHA vertical orthogonal scaffold (S1), (b)
PLA/nHA staggered orthogonal scaffold (S2), (c)
PLA/nHA/CS-Van vertical orthogonal scaffold (S3) and (d)
PLA/nHA/CS-Van staggered orthogonal scaffold (S4) (Gao
et al. 2023) Copyright 2023, RSC
In conclusion, nanomedicine and tissue
engineering approaches have shown great promises
in orthopaedics. In recent years, 3D bioprinting of
bone mimicking scaffolds comprised of polymer
(e.g., polylactic acid, polycaprolactone), and
inorganic NPs (e.g., reduced graphene oxide,
hydroxyapatite/chitosan) have emerged as potential
candidate systems for bone tissue engineering
(Seyedsalehi et al. 2020; Zhang et al. 2021). This
chapter covered the applicability of these scaffolds
in promoting scaffold fidelity, osteogenic
differentiation and mineralization.

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S. Tamil Selvan, Nanomedicine, Nanotheranostics
https://doi.org/10.1007/978-981-99-2139-3_5

5. Nanomedicine for Cardiac

Diseases
Subramanian Tamil Selvan 1
(1) Alpha Biomedical Pte. Ltd., Singapore,
Singapore

Subramanian Tamil Selvan

Email: [email protected]

Abstract
Nanomedicine is a rapidly developing field with the
potential to transform the treatment of cardiac
diseases. It entails the use of nanoscale materials
and devices to diagnose, treat, and prevent a variety
of cardiovascular diseases. The development of
nanocarriers for drug delivery is a key application of
nanomedicine in cardiology. This chapter delineates
the applications of nanomedicine in diagnostics and
treatment of cardiovascular diseases.

Keywords Nanomedicine – Cardiovascular diseases

– Dual drug delivery – Dextran NPs – Cardiac tissue
repair – Nanoparticle/composite patch – Exosomes –
Stem cells – Cardiac regeneration
Cardiovascular diseases or disorders (CVDs) are one
of the leading causes of significant morbidity and
mortality. The increasing mortality rate is often
attributed to hypertension, a key factor for the onset
of CVDs such as myocardial infarction,
atherosclerosis, thrombosis, and restenosis. Among
these CVDs, atherosclerosis (thickening of the
arterial vessel wall due to build-up of fats,
cholesterol), myocardial infarction (heart attack),
coronary artery disease, and arrhythmias (irregular
heartbeat) are considered as the main causes of
heart failure. This requires the development of novel
diagnostic and therapeutic methods for chronic
heart failure (Haeck et al. 2012). Although
considerable progress has been made over the years
in imaging modalities such as magnetic resonance
imaging (MRI) and computed tomography (CT),
diagnostic nanomedicine aims to improve the early
detection by using nanoparticle-based contrast
agents for better visualization of the heart and blood
vessels.

5.1 Nanomedicine for Diagnostics

and Therapeutics of CVDs
Nanomedicine has a great potential for the
diagnostics and treatment of CVDs. Nanomedicine
based therapeutics and molecular imaging methods
emerge as novel strategies in addressing the
morbidity and mortality associated with myocardial
infarction (Ferreira et al. 2015). Nanomedicine
enables controlled delivery of active drugs
encapsulated in nanocarriers for targeted delivery
into the vascular site. This targeted nanomedicine
approach is increasingly used for the treatment of
CVDs like the dissolution of atherosclerotic plaques
accumulated in the coronary arteries walls
(Kleinstreuer et al. 2018).

5.1.1 Nanomedicine for Cardiac

Tissue Repair and Reinforcement
Importantly, nano/biomaterials combined with stem
cells offer great promises for cardiac tissue repair
and reinforcement (Hasan et al. 2016; Tariq et al.
2022). Direct delivery of cardioprotective drugs
(e.g., adenosine) into the ischemic-reperfused
myocardium poses great challenges. Biodegradable
silica nanoparticles have been used as carriers for
the delivery of adenosine into ischemic-reperfused
heart tissue (Galagudza et al. 2012).
Recently, several reviews focused on addressing
novel nanoparticles (NPs) and nanomedicine
approaches for early disease diagnosis (e.g.,
molecular imaging) and advanced therapeutic (e.g.,
drug eluting stents) applications of CVDs such as
restenosis, atherosclerosis, and MI (Godin et al.
2010; Chopra et al. 2022; Mohamed et al. 2022;
Ouyang et al. 2022; Saeed et al. 2023).
Oxidative stress induced free radicals are closely
associated with atherosclerosis and many other
heart diseases. Polymeric PLGA NPs loaded with an
antioxidant drug quercetin, improved the
bioavailability of the drug, and prevented the
atherosclerosis (Giannouli et al. 2018).
Biodegradable porous silicon NPs functionalized
with atrial natriuretic peptide and loaded with a
cardioprotective small molecule reduced the
hypertrophic signaling in the endocardium,
demonstrating the targeted delivery of drug to the
injured region of the myocardium (Ferreira et al.
2017).

5.1.2 Nanocarriers for Cardiac

Delivery of Drugs and MicroRNA
Calcium phosphate NPs have been emerged as
therapeutic vehicles for cardiac delivery of
MicroRNAs (Di Mauro et al. 2016). Studies have
shown that calcium phosphate NPs can be
internalized and delivered microRNAs efficiently into
cardiac cells (cardiomyocytes) both in vitro and in
vivo.
Interestingly, NPs have also been used as
protective agents to minimize the cardiac toxicity
and disorders associated with oxidative stress. For
instance, cerium oxide NPs showed a promising
ameliorative and prophylactic toxicity effect,
compared to the reference drug, Captopril (El Shaer
et al. 2017). Vesicles such as exosomes (< 100 nm)
could serve as vehicles for lipids, proteins, DNA and
RNAs, and therefore, offers new insights into
personalized nanomedicine for acute cardiac, lung,
and kidney injury (Terrasini and Lionetti 2017).
 Nanotechnology-based diagnostics and
therapeutics using mesoporous silica NPs have been
used to study the heart failure in cardiac tissue of a
murine heart failure model. After intravenous
administration, these nanovectors were found to be
internalized and accumulated in failing myocardium,
through the labelling of perinuclear region of
cardiomyocytes in vivo (Ruiz‐Esparza et al. 2016).
Other diseases and their treatment methods are
closely associated to heart failure. For instance,
anticancer drugs are prone to exhibit toxicity to
cardiac cells. However, when DOX is encapsulated
within exosomes, no cardiac toxicity observed from
in vivo studies, resulting in about 40% of
accumulation of exosome-DOX in the heart (Toffoli et
al. 2015). The detoxifying action of liposomes was
demonstrated in a mouse cardiovascular model
(Bertrand et al. 2010).
Nanomedicine offers great potential in cardiac
catheterization via targeted drug delivery, while
preventing the endothelial dysfunction or damage of
cells by reduced inflammation or increased nitric
oxide bioavailability (Sobolewski and El Fray 2015).
The sustained delivery of cardiac therapeutics
[Pyr1]-apelin-13 polypeptide in vivo for treating
heart injuries was achieved by PEG-conjugated
liposomal NPs. The cardiac dysfunction was
prevented by this approach through the sustained
bioavailability of cardio-protective therapeutics
(Serpooshan et al. 2015).
5.2 Nanotechnology Assisted Cardiac
Regenerative Medicine
Cardiac regenerative medicine is an emerging
paradigm. Carbon nanotubes (CNTs) have received
considerable interest in cardiovascular system,
owing to its remarkable characteristics in promoting
in vitro growth of cardiac cells and improving
proliferation, maturation, and electrical behaviour of
cardiomyocytes (Martinelli et al. 2013). Myocardial
tissues cultured on the CNT–GelMA (gelatin
methacrylate) hydrogel scaffold showed high
mechanical strength and electro-activity with
spontaneous synchronous beating rates, compared
to those cardiac tissues cultured on pristine GelMA
hydrogels (Shin et al. 2013).
Magnetic bifunctional NPs conjugated with
antibodies were used for treating acute myocardial
infarction through the targeting of CD45 expressing
stem cells (exogenous bone marrow-derived) or
CD34-positive cells (endogenous injured
cardiomyocytes) (Cheng et al. 2014). Methacrylated
gelatin biocompatible hydrogel was used as a
delivery vehicle to deliver polyethylenimine (PEI)
functionalized graphene oxide nanosheets
complexed with a pro-angiogenic gene—vascular
endothelial growth factor (VEGF) for myocardial
therapy (Paul et al. 2014). This nanocomposite
approach showed significant cardiac performance in
echocardiography after 14 days of post-injection.
The nanocomposite treated infarcted hearts showed
a reduction in scar area.
Early allograft acute rejection in heart
transplantation is a big problem. Simultaneous
diagnosis by non-invasive MRI and gene therapy
(mediating gene transfection in T cells) by
multifunctional polymeric nanocarriers provided a
great relief in heart-transplanted rats (Guo et al.
2012). Nanopatterned (nanofibrous electro-spun)
cardiac patches prevented defective electro-coupling
and improved the therapeutic efficacy of myocardial
infarction, thereby opening avenues in translational
myocardial tissue engineering and nanomedicine
(Lin et al. 2014).
Cobalt protoporphyrin encapsulated amine‐
functionalized mesoporous silica NPs
(CoPP@aMSNs)—labelled bone marrow stromal cells
(BMSCs) have been synthesized (Fig. 5.1) and
exhibited photoacoustic imaging (PA) enhancement
—guided cell delivery and antioxidant protection of
stem cells. (Yao et al. 2018) The drug, CoPP released
upon MSN degradation, and endowed the labelled
BMSCs with persistent antioxidant activity.
Fig. 5.1 Schematic representation of cobalt
protoporphyrin encapsulated mesoporous silica NPs
(CoPP@aMSNs)‐labelled BMSCs for implantation and cell
protected therapy guided by photoacoustic (PA) imaging.
TAT peptide facilitates the cell internalization. Reproduced
with permission (Yao et al. 2018). Copyright 2018, Wiley-
VCH
The mouse myocardium implanted with NPs -
labelled BMSCs using an insulin needle and analysed
by both ultrasound and photoacoustic imaging (Fig.
5.2a–d). The photoacoustic imaging observed at the
laser excitation of 680 nm revealed clearly the
implanted stem cells (Fig. 5.2a, b). The histological
hematoxylin and eosin (H&E) staining of the
dissected myocardium after 24 h post-injection
showed the engrafted BMSCs corresponding to the
enhanced photoacoustic signal region (Fig. 5.2c).
Nevertheless, the photoacoustic imaging (Fig. 5.2e,
f) showed the leakage of implanted BMSCs into
pericardial cavity, indicating the unsuccessful intra-
myocardial implantation.

Fig. 5.2 The ultrasound and photoacoustic images of the

cardiac structure before (a) and after (b) intra-myocardial
injection of BMSCs. The white curves in the ultrasound
images denote the outline of the myocardium, whereas the
yellow arrow indicates the strengthened photoacoustic
signal from the injected particles. The line patterns at the
bottom show the ECG and respiratory coupling signals of
nude mouse. c Haemotoxylin and Eosin (H&E) stained
microscopic image of the BMSCs (blue) in the myocardium.
d The ultrasound image process of the intramyocardial
injection using 30 G needle. e, f The long‐axis view of
cardiac structures before (e) and after (f) intramyocardial
injection of the labelled BMSCs with the signal (dotted
circle, f) corresponding to the leaked BMSCs in the
pericardial cavity. The H&E staining of different organ
sections of nude mice for the control (g: Matrigel/saline
solution) and labelled BMSCs (h) taken on day 28.
Reproduced with permission (Yao et al. 2018). Copyright
2018, Wiley-VCH
On a positive note, CoPP@aMSNs‐labelled BMSCs
did not cause any acute toxicity and pathological
abnormalities to all major organs (liver, spleen,
heart, lung and kidney) after 4 weeks of intra-
myocardial injection, indicting the biosafety of this
nanomedicine strategy (Fig. 5.2g, h).

5.2.1 Dextran NPs Assisted Dual

Drug Delivery for Cardiac
Regeneration
Cardiac regeneration holds great promise in
restoring the full functionality of a damaged heart.
However, it remains a challenge as the injured or
damaged heart contains a vast number of fibroblasts
and myofibroblasts. To replenish the lost
cardiomyocytes, a direct fibroblast cell
reprogramming into cardiomyocytes is regarded as
an attractive therapeutic option. For this purpose,
two small drug molecules, CHIR99021
(aminopyrimidine derivative for glycogen synthase
kinase, enzyme GSK-3 inhibitor) and SB-431542 (a
drug developed by GlaxoSmithKline for activin
receptor-like kinase, ALK5, ALK4 and ALK7
inhibitor) were encapsulated into dextran NPs
(functionalized with polyethylene glycol and atrial
natriuretic peptide for pH-triggered drug delivery
into the affected areas for direct reprogramming of
fibroblast into cardiomyocytes (Ferreira et al. 2018).

5.2.2 Nanotherapeutic Approach for

Alleviating Cardiac Brain Injury
Another important issue is cardiac
arrest/cardiopulmonary resuscitation (CA/CPR)-
induced brain injury, which necessitates feasible
therapeutic options. To address this, a
nanotherapeutic approach based on octanoic acid
(OA) and a neutrophil membrane expressing RVG29,
RVG29-H-NP-OA has recently been developed for
ameliorating the CA/CPR-induced brain injury (Yang
et al. 2023). Peptide (RVG29-rabies virus
glycoprotein) conjugated OA-NP traversed BBB and
targeted the injured brain. Due to their antioxidant,
mitochondria stability and anti-inflammatory effects
of OA, RVG29-H-NP-OA significantly improved the
survival rate and neurological functions of CA/CPR
model rats from 40% to 100% over 24 h (Fig. 5.3).
Fig. 5.3 A schematic representation of brain injury relay
targeting nanotherapeutic approach based on octanoic acid
(OA) and a neutrophil membrane expressing RVG29
peptides for improving the cardiac arrest/cardiopulmonary
resuscitation-induced brain injury (Yang et al. 2023).
Copyright 2023, ACS

5.2.3 Nanoparticle-Based Composite

Patch for Myocardial Infarction
Myocardial infarction, generally identified as heart
attack, occurs when blood flow to one or more areas
of the heart muscle is blocked. Coronary artery
disease is the main cause of myocardial infarction.
Cardiac delivery of therapeutic agent may serve as a
promising platform for the treatment of heart
diseases. Toward this end, nanocarriers have been
developed for efficient delivery of therapeutic agents
to target the heart. Earlier, porous silicon-based
nanomaterials have been used for both diagnostic
and therapeutic applications (Li et al. 2018; Tieu et
al. 2019). Although biocompatible porous silicon
based multifunctional drug delivery systems (DDS)
have been widely used for cancer therapy (Zhang et
al. 2019), their application in cardiac tissue
engineering is limited. Porous silicon micro and
nanoparticles showed in vivo biocompatibility to the
heart tissue (Tölli et al. 2014).
Recently, a biodegradable polymer (polyglycerol
sebacate) nanoparticle conductive composite patch
loaded with a small molecule (3i-1000) drug, has
been developed for treating myocardial infarction
(Zanjanizadeh Ezazi et al. 2020). This nanocomposite
contained collagen type I to promote cell
attachment, and polypyrrole for inducing electrical
conductivity and cell signaling (Fig. 5.4).

Fig. 5.4 A schematic representation of the synthesis of

elastic biodegradable and conductive cardiac patches.
Polycondensation of sebacic acid and glycerol was used to
prepare polyglycerol sebacate (PGS). Natural polymer
(collagen type I) and conductive polymer (polypyrrole PPy)
were added. The composite polymer was cured at high
temperature under vacuum, resulting in a conductive
biodegradable heart patch (Zanjanizadeh Ezazi et al. 2020).
Copyright 2020, ACS
Cardiomyoblast cell attachment and morphology
on the surface of cardiac patches were observed
using a scanning electron microscope (SEM) (Fig.
5.5). High infiltration and attachment of
cardiomyoblast cells were found on the collagen-
containing patches (0.5C–5P) within 24 h.
Fig. 5.5 SEM images of cardiomyoblast morphology upon
cell attachment on the surface of a 0C–0P, b 0C–1P, c 0.5C–
0P, and d 0.5C–5P patches on the control (non-conductive)
and conductive samples during 24 h. Collagen-containing
patches showed high infiltration and attachment on 0.5C–
5P patches within 24 h. Scale bar: 100 μm (Zanjanizadeh
Ezazi et al. 2020). Copyright 2020, ACS
The in vitro experiments confirmed that a high
density of cardiac myoblast cells was attached on the
patches, which remained viable for > 1 month.
Conductive patches showed high drug release with
no cytotoxic effect upon degradation of the patches,
and cell proliferation was induced by the small
molecule drug.
A recent work on magnetic-guided accumulation
of exosomes suggested that the antibody-conjugated
magnetic NPs can be used to capture and deliver
circulating CD63-expressing exosomes in infarcted
heart tissue, leading to reductions in infarct size as
well as improved angiogenesis in rat models of
myocardial infarction (Liu et al. 2020).
In conclusion, this chapter reviewed the recent
developments of nano/biomaterials having the
attributes of mechanical, conductive, and biological
requirements for a successful cardiac treatment.

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© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2023
S. Tamil Selvan, Nanomedicine, Nanotheranostics
https://doi.org/10.1007/978-981-99-2139-3_6

6. Conclusions and
Perspectives
Subramanian Tamil Selvan 1
(1) Alpha Biomedical Pte. Ltd., Singapore,
Singapore

Subramanian Tamil Selvan

Email: [email protected]

Abstract
This chapter summarises the applications of
nanomedicine in diagnostics and therapeutic
approaches for cancer, neurodegenerative diseases,
cardiovascular diseases, and orthopaedics related
bone tissue engineering.

Keywords Nanomedicine – Cancer – Cardiovascular

diseases – Orthopaedics – Neurodegenerative
diseases – Drug delivery – Nanomaterials –
Combination immunotherapy – Multifunctional
nanoparticles – Liposomes – Targeted delivery
In this Brief, we have extensively covered different
types of emerging nanomaterials and nanoparticles
(NPs) as theranostic tools for cancer,
neurodegenerative, orthopaedic, and cardiac
diseases. Over the years, there have been enormous
research efforts in nanomaterials, aiming to create
new scientific fields with interdisciplinary
approaches covering chemistry, physics,
bioengineering, and medicine. However, the field of
nanomedicine is still in its infancy state, which
necessitates active collaboration with different
fraternities with diverse expertise to tackle the
challenges of these burgeoning diseases.
Cancer remains an elusive disease and therefore
it is a major health challenge worldwide.
Nanomedicine has greatly contributed to cancer in
the form of imaging agents, and drug delivery
carriers. However, there are many challenges to be
addressed. The tumor microenvironment is a key
factor which helps the cancer cells proliferate,
invade with metastasis and drug resistance. This
evades the cancer cell to be killed by the common
treatments such as chemotherapy, radiotherapy, and
surgery. This necessitates the development of a
cancer therapy resistance especially in solid tumors.
Recently, cancer nanomedicine offers a great
advantage in targeting the tumor microenvironment
and treating drug resistance through the
advancements in NPs (Sa et al. 2023).
Importantly, NP-based delivery systems have
been developed for cancer immunotherapy.
Combination immunotherapy is a growing field,
which uses the NP-assisted therapies (photothermal,
photodynamic and radiotherapy) for targeting and
controlling the immunosuppressive cells (including
T-cells, dendritic cells, tumour-associated
macrophages, etc.) in the tumour microenvironment
(Nam et al. 2019; Yoon et al. 2018). Mesoporous
silica NP still emerges as a potential platform for
incorporating MEK inhibitor (MEK: mitogen-
activated protein kinase enzyme) and anti‐PD‐1
antibody (PD: programmed cell death protein;
checkpoint protein on immune T cells) for combined
targeted therapy and immune checkpoint blockade
(Liu et al. 2019).
Novel genetic nanomedicines based on a
multifunctional nanodevice (lipid NPs, GALA peptide
and siRNA) enabled selective lung targeting by the
judicious control of lipid NP composition, and
improved lung endothelium CD31 gene silencing,
thereby achieving efficient therapy for metastatic
lung cancer (Abd Elwakil et al. 2019).
The MRI is a powerful non-invasive tool for early
and accurate diagnosis of Alzheimer’s disease (AD)
with behavioural changes and cognitive impairment.
Recent years have witnessed significant research
activities in the development of NP-based contrast
agents functionalized with antibodies, peptides or
small molecules for brain MRI (Azria et al. 2017).
The ability to target amyloid plaques depends on the
size, composition of NPs and their ability to cross the
blood–brain-barrier (BBB).
 Another emerging nanomaterial is black
phosphorus. It can serve not only as a carrier for
drugs but also as a neuroprotective agent for
neurodegenerative diseases (Ge et al. 2019). Besides
brain biomarkers, peripheral blood and skin tissues
emerge as potential prognostic biomarkers for
probing the disease pathology in neurodegenerative
diseases. The application of nanomedicine in the
form of scaffolds, drug delivery and imaging systems
has effectively improved the neural stem cell-based
treatments for neurodegenerative diseases.
As regards orthopaedic and cardiac diseases,
nanomedicine-assisted stem cell therapy is an
interesting paradigm. One of the notable findings in
bone regeneration is the demonstration of articular
cartilage implant for osteoarticular regeneration,
which utilises nanofibrous poly-ε-caprolactone (PCL)
and BMSCs in alginate/hyaluronic acid hydrogel
(Keller et al. 2019). This work may enter into phase I
clinical trials with the potential of treatment for
osteochondral defects, tendon degeneration and age-
related musculoskeletal degenerative issues.
Nanomedicine provides advantages in imaging-
guided stem cell transplantation and therapy. A
notable work is on a multifunctional nanoplatform
encompassing mesoporous silica NP and cobalt
protoporphyrin (antioxidant drug) for photoacoustic
imaging-guided cell delivery and antioxidant
protection of stem cells (Yao et al. 2018). This
method allows for monitoring specific labelling and
delivery of stem cells in myocardial tissues with the
advent of photoacoustic imaging.
 Current gene editing technology based on
engineered nucleases such as clustered regularly
interspaced short palindromic repeat (CRISPR)–Cas
nucleases combined with Au NPs paves a safer way
in treating numerous diseases associated with stem
and progenitor cells (Shahbazi et al. 2019) This
combined nano/gene editing approach obviates the
difficulties associated with the current cellular
entries such as electroporation, and virus
transduction. Nanotechnology mediated gene editing
emerges as an efficient delivery vehicle for CRISPR
nucleases of therapeutic interest.
Although nanomaterials provide numerous
benefits, we cannot rule out their disadvantages. For
instance, a recent study cautioned the negative side
of carbon nanotubes (CNTs). When multiwall CNTs
(MWCNTs) introduced into the CNS, they induced
higher expression of neuronal nitric oxide synthase
in cardiovascular medulla, attenuating sympathetic
nerve activity and causing hypotension (low blood
pressure and heart rate) (Ma et al. 2018). On the
other hand, black phosphorus nanosheets can be
used to protect neuronal cell from damage by
harvesting Cu2+ ions with their strong binding,
thereby reducing the cytotoxic ROS generation and
copper dyshomeostatis (Ge et al. 2019).
Nanomedicine has attracted widespread interest
in recent years, thanks to the emergence of novel
nano/biomaterials. Some of the recent
advancements include 2D nanomaterials for
photothermal therapy (Lin et al. 2017; Cheng et al.
2020; Liu et al. 2020a, b, c), multifunctional Au-
based nanomaterials for enhanced cancer
radiotherapy (Zhang et al. 2018; Wang et al. 2023),
chemo/photothermal synergistic cancer therapy (Liu
et al. 2020a, b, c; Chang et al. 2022; Ouyang et al.
2023), and synergistic hyperthermia/immunotherapy
(Chang et al. 2021).
A brief introduction (Chap. 1) is given to
nanomedicine, an emerging paradigm intersecting
two burgeoning fields of nanotechnology and
medicine. Different functional nanomaterials,
nanocomposites and nanostructures are discussed
for diagnostics and therapeutic applications of
cancer, cardiovascular, orthopaedics, and
neurodegenerative disorders.
In Chap. 2, we have delineated various
multifunctional QDs, magnetic NPs and Au-based
nanostructures for bioimaging and therapy.
Inorganic NPs or organic polymer mediated drug
delivery vehicles and liposomes for targeted delivery
are discussed. We have also discussed cancer
nanomedicine and their promises in preoperative
therapeutics, neoadjuvant radiotherapy,
chemotherapy, phototherapy, and immunotherapy.
In Chap. 3, we have discussed different
nanomedicine approaches for neurodegenerative
diseases such as Alzheimer’s disease (AD). Several
NP-based strategies (e.g., Au-curcumin, PEG-Au
NPs,) are addressed to prevent amyloid fibrillation
and tau protein hyper-phosphorylation, so that
apoptosis and neurodegeneration can be inhibited.
Cerium oxide or ceria (CeO2) NPs can be used as an
effective antioxidant for various neurodegenerative
diseases including Alzheimer’s and Parkinson’s
diseases, ischemic stroke, and multiple sclerosis.
In Chap. 4, we have discussed the emerging
applications of nanomedicine and tissue engineering
approaches in orthopaedics. Bone mimicking
scaffolds composed of biocompatible and
biodegradable polymers such as polylactic acid and
polycaprolactone, and inorganic NPs (e.g., reduced
graphene oxide, hydroxyapatite/chitosan) have
shown great promises in bone tissue engineering by
enhancing scaffold fidelity, osteogenic
differentiation, and mineralization.
In Chap. 5, we have discussed the applications of
nanomedicine in diagnostics and treatment of
cardiovascular diseases (CVDs). Notably, antibody-
conjugated magnetic NPs have been used to capture
and deliver circulating CD63-expressing exosomes to
the infarcted heart tissue in rat models of myocardial
infarction (Liu et al. 2020a, b, c) This magnetic-
guided accumulation of exosomes in infarcted tissue
led to reductions in infarct size as well as improved
angiogenesis.
Although nanomaterials have great potential for
the diagnosis of cancer, cardiac and
neurodegenerative diseases, their therapeutic
potential is a big question mark owing to their
unknown toxicity concerns in the end. Nevertheless,
numerous in-vivo studies demonstrated that they are
safe and cleared from the body. Compared to
inorganic nanomaterials, organic based liposomes,
lipids, and biodegradable chitosan NPs and FDA-
approved polymers are quite safe to unravel the
mysteries of the biological world.
Interestingly, polysaccharide-based drug delivery
systems have been utilized for orthopaedic
treatments and controlled delivery of anticancer
drugs (Hormozi 2023) Furthermore, naturally
occurring biocompatible NPs and polymers can be
used to deliver anticancer drugs, proteins, peptides,
and other genetic materials such as miRNA, siRNA,
etc. (Ahmad et al. 2022).
Despite the promise of nanomedicine for the
treatment of cardiac diseases, there are also
challenges that must be overcome. For example, the
potential toxicity of NPs must be carefully evaluated,
and the long-term effects of nanomedicine
treatments must be thoroughly studied.

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