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Collection Highlights

Cancer Nanotheranostics Volume 2 Nanotechnology in the

Life Sciences Muthupandian Saravanan

Introductory Physics for the Life Sciences: Mechanics

(Volume One) David V Guerra

Blockchain in Life Sciences Wendy Charles

Mutants and Masterminds Hero High 3rd Edition Lucien

Soulban With Prof Christopher Mcglothlin M Ed
Magic Awaken Magic Bound 2 1st Edition J E Cluney

Distributed Artificial Intelligence Third International

Conference DAI 2021 Shanghai China December 17 18 2021
Proceedings 1st Edition Jie Chen

An Introduction to Analysis 1st Edition Robert C Gunning

Tourism Products and Services in Bangladesh Concept

Analysis and Development Suggestions 1st Edition Azizul
Hassan

Dawn s Promise A W Exley

Schemes of Arrangement Theory Structure and Operation 2nd
Edition Jennifer Payne
Nanotechnology in the Life Sciences

Muthupandian Saravanan
Hamed Barabadi Editors

Cancer
Nanotheranostics
Volume 1
Nanotechnology in the Life Sciences

Series Editor
Ram Prasad
Department of Botany
Mahatma Gandhi Central University
Motihari, Bihar, India
Nano and biotechnology are two of the 21st century’s most promising technologies.
Nanotechnology is demarcated as the design, development, and application of
materials and devices whose least functional make up is on a nanometer scale (1 to
100 nm). Meanwhile, biotechnology deals with metabolic and other physiological
developments of biological subjects including microorganisms. These microbial
processes have opened up new opportunities to explore novel applications, for
example, the biosynthesis of metal nanomaterials, with the implication that these
two technologies (i.e., thus nanobiotechnology) can play a vital role in developing
and executing many valuable tools in the study of life. Nanotechnology is very
diverse, ranging from extensions of conventional device physics to completely new
approaches based upon molecular self-assembly, from developing new materials
with dimensions on the nanoscale, to investigating whether we can directly control
matters on/in the atomic scale level. This idea entails its application to diverse fields
of science such as plant biology, organic chemistry, agriculture, the food industry,
and more.
Nanobiotechnology offers a wide range of uses in medicine, agriculture, and the
environment. Many diseases that do not have cures today may be cured by
nanotechnology in the future. Use of nanotechnology in medical therapeutics needs
adequate evaluation of its risk and safety factors. Scientists who are against the use
of nanotechnology also agree that advancement in nanotechnology should continue
because this field promises great benefits, but testing should be carried out to ensure
its safety in people. It is possible that nanomedicine in the future will play a crucial
role in the treatment of human and plant diseases, and also in the enhancement of
normal human physiology and plant systems, respectively. If everything proceeds as
expected, nanobiotechnology will, one day, become an inevitable part of our
everyday life and will help save many lives.

More information about this series at http://www.springer.com/series/15921

Muthupandian Saravanan • Hamed Barabadi
Editors

Cancer Nanotheranostics
Volume 1
Editors
Muthupandian Saravanan Hamed Barabadi
AMR and Nanomedicine Lab Department of Pharmaceutical
Department of Pharmacology Biotechnology, School of Pharmacy,
Saveetha Dental College Shahid Beheshti University
Saveetha Institute of Medical and of Medical Science
Technical Sciences (SIMATS) Tehran, Iran
Chennai, India

ISSN 2523-8027     ISSN 2523-8035 (electronic)

Nanotechnology in the Life Sciences
ISBN 978-3-030-74329-1    ISBN 978-3-030-74330-7 (eBook)
https://doi.org/10.1007/978-3-030-74330-7

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2021
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The publisher, the authors, and the editors are safe to assume that the advice and information in this book
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Preface

Nanotechnology is an interdisciplinary research field that integrates chemistry,

engineering, biology, and medicine. Nanomaterials offer tremendous opportunities
as well as challenges for researchers. Of course, cancer is one of the world’s most
common health problems, responsible for many deaths. Exploring efficient antican-
cer drugs could revolutionize treatment options and help manage cancer mortality.
Nanomedicine plays a significant role in developing alternative and more effective
treatment strategies for cancer theranostics. This book mainly focuses on the emerg-
ing trends using nanomaterials and nanocomposites as alternative anticancer mate-
rials. The book is divided into three main topic areas: how to overcome existing
traditional approaches to combat cancer, applying multiple mechanisms to target
the cancer cells, and how nanomaterials can be used as effective carriers. The con-
tents highlight recent advances in interdisciplinary research on processing, mor-
phology, structure, and properties of nanostructured materials and their applications
to combat cancer.
Cancer Nanotheranostics is comprehensive in that it discusses all aspects of can-
cer nanotechnology. Because of the vast amount of information, it was decided to
split this material into two volumes. In the first volume of Cancer Nanotheranostics,
we discuss the role of different nanomaterials for cancer therapy, including lipid-
based nanomaterials, protein and peptide-based nanomaterials, polymer-based
nanomaterials, metal-organic nanomaterials, porphyrin-based nanomaterials, metal-
based nanomaterials, silica-based nanomaterials, exosome-based nanomaterials,
and nano-antibodies. In the second volume, we discuss the nano-based diagnosis of
cancer, nano-oncology for clinical applications, nano-immunotherapy, nano-based
photothermal cancer therapy, nano-erythrosomes for cancer drug delivery, regula-
tory perspectives of nanomaterials, limitations of cancer nanotheranostics, the

v
vi Preface

safety of nano-biomaterials for cancer nanotheranostics, multifunctional nanomate-

rials for targeting cancer nanotheranostics, and the role of artificial intelligence in
cancer nanotheranostics.

Mekelle, Ethiopia Muthupandian Saravanan

Tehran, Iran Hamed Barabadi
Contents

1 Targeted Nanotheranostic Systems in Cancer Therapy ����������������������    1

Avneet Kour, Aman Tiwari, Jiban Jyoti Panda,
and Jibanananda Mishra
2 Dual Targeting Drug Delivery for Cancer Theranostics����������������������   31
Ghassem Amoabediny, Ghazal Rastegar, Mahin Maleki, Dina Jafari,
Zeynab Amoabediny, Fardin Rahimi, and Mina Khodarahmi
3 Cancer Nanotechnology for Drug Targeting and Delivery
Approaches ����������������������������������������������������������������������������������������������   53
Vadivel Siva, Chunchana Kuppe Renuka Prasad Ravikumar,
Ponnusamy Thillai Arasu, Nagendra Nath Yadav,
Arumugam Murugan, Hardeo Singh Yadav, Sultan Asath Bahadur,
and Saminathan Balamurali
4 Camelid Single-Domain Antibodies for Targeting Cancer
Nanotheranostics��������������������������������������������������������������������������������������   93
Sepideh Khaleghi, Shahryar Khoshtinat Nikkhoi,
and Fatemeh Rahbarizadeh
5 Emerging Lipid-Based Nanomaterials for Cancer Theranostics�������� 125
Humzah Jamshaid and Fakhar-ud-Din
6 Emerging Protein and Peptide-Based Nanomaterials
for Cancer Therapeutics�������������������������������������������������������������������������� 161
Samraggi Choudhury, Nidhi Aggarwal, Jiban Jyoti Panda,
and Jibanananda Mishra
7 Emerging Polymer-Based Nanomaterials
for Cancer Therapeutics�������������������������������������������������������������������������� 189
Chandan Gupta, Abhay Uthale, Tanuja Teni, Premlata Ambre,
and Evans Coutinho

vii
viii Contents

8 Emerging Metal-Organic Framework Nanomaterials

for Cancer Theranostics�������������������������������������������������������������������������� 231
Elham Asadian, Mahnaz Ahmadi, Rüstem Keçili,
and Fatemeh Ghorbani-Bidkorbeh
9 Porphyrin-Based Nanomaterials for Cancer Nanotheranostics���������� 275
Md. Habban Akhter, Javed Ahmad, Md. Noushad Javed,
Rafiul Haque, Habibullah Khalilullah, Manish Gupta,
and Javed Ali
10 The Emerging Role of Exosomes as Cancer Theranostics ������������������ 297
Gilar Gorji-Bahri and Atieh Hashemi
11 Emerging Theragnostic Metal-Based Nanomaterials
to Combat Cancer������������������������������������������������������������������������������������ 317
Sivasubramanian Manikandan, Ramasamy Subbaiya,
Muthupandian Saravanan, Hamed Barabadi,
and Ramaswamy Arulvel
12 Emerging Lipid-Coated Silica Nanoparticles
for Cancer Therapy���������������������������������������������������������������������������������� 335
Achraf Noureddine, Joseph D. Butner, Wei Zhu, Paulina Naydenkov,
María J. Peláez, Shreya Goel, Zhihui Wang, C. Jeffrey Brinker,
Vittorio Cristini, and Prashant Dogra
Chapter 1
Targeted Nanotheranostic Systems
in Cancer Therapy

Avneet Kour, Aman Tiwari, Jiban Jyoti Panda, and Jibanananda Mishra

Contents
1.1 I ntroduction 1
1.2 N  anotheranostics 2
1.2.1 Different Types of Nanotheranostics 4
1.3 Specific Applications of Cancer-Targeted Nanotheranostics 12
1.3.1 Nanotheranostics Application in Personalized Cancer Therapy 12
1.4 Conclusion 22
References 22

1.1 Introduction

Cancer is an unconquerable ailment due to its multitudinous characteristics that

might be triggered by various endogenous and exogenous factors. It is the second
major cause of the mortality worldwide accounting for approximately 9.6 million
deaths in 2018, which is prognosticated to exceed cardiac complications, consid-
ered to be the major reason for death worldwide (WHO). The predominant cause of
cancer-related death worldwide accounts to lung cancer that causes approximately
1.76 million deaths followed by colorectal cancer (862,000 deaths), stomach cancer
(783,000 deaths), liver cancer (782,000 deaths), and breast cancer (627,000 deaths).
In low- and middle-income countries, approximately 70% of deaths occur due to
cancer, and the number of cancer patients is speculated to rise to 21 million by 2030
(WHO; Bhakta-Guha et al., 2015). Cancer causes a huge financial burden due to the
economic cost of treatment and palliative concern. The yearly economic cost of
cancer in 2015 was estimated to be approximately US$ 100 billion (Herper, 2015).

A. Kour · A. Tiwari · J. J. Panda ()

Institute of Nano Science and Technology, Punjab, India
e-mail: [email protected]
J. Mishra ()
AAL Biosciences Research Pvt. Ltd., Haryana, India

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 1

M. Saravanan, H. Barabadi (eds.), Cancer Nanotheranostics, Nanotechnology in
the Life Sciences, https://doi.org/10.1007/978-3-030-74330-7_1
2 A. Kour et al.

Thus, these demand for the exploration of better, safer, and more efficient therapeu-
tic and diagnostic approaches for combating the disease.
There have been significant advancements in cancer therapy, and various
advanced treatment procedures have decreased the number of cancer deaths (Roy
Chowdhury et al., 2016). Conventional cancer treatment procedures involve surgery
(thoracoscopic, laparoscopic, endoscopic, laser), immunotherapy, chemotherapy,
stem cell transplant therapy, and radiotherapy (Howell & Valle, 2015). Chemotherapy
combats cancers (lung cancer, sarcoma, breast cancer, myeloma) by the intake of
the drugs. Radiotherapy (image-guided, four-dimensional conformal and intensity-­
modulated) interferes in the progression of various types of cancers (prostate, head,
breast, neck) (Bucci et al., 2005). Various cancer immunotherapeutics modulate the
immune systems which are responsible for causing the malignancy. However, these
treatment approaches suffer from manifold side effects. The current-day treatment
approaches for the disease often entail invasive methods and exhibit drug resistance
and systemic toxicity.
Apart from therapeutics, various approaches have been developed for the diag-
nosis of the tumors so that effective therapeutic regimen can be proposed like x-ray,
ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI),
and nuclear scan. Regardless of the numerous approaches for the diagnosis of can-
cer, there are still various limitations that need to be addressed before realizing the
proper and early detection of the disease. However, ameliorated diagnostic and
therapeutic perspectives have increased the survival rate of patients suffering from
cancer, but still complete riddance of the disease is improbable. Therefore, it
becomes inevitable to explore and find novel approaches to diagnose and treat can-
cer more effectively. One such novel arena for effective treatment as well as diagno-
sis of cancer is nanotheranostics.

1.2 Nanotheranostics

A nanoparticle carries great potential in cancer due to their selectivity and tumor-­
homing approaches. These can be easily surface fabricated with the cancer-targeting
ligands, thereby reducing side effects. These have enhanced in vivo circulation
duration that reduces the frequency of administration and thus improves patient
compliance. Thus, owing to these benefits, nanoparticles are considered as a poten-
tial therapeutic platform for the therapy of cancer.
In 2002, John Funkhouser coined the term “theranostics” to represent the diag-
nosis and therapeutic activity simultaneously to cure the ailment (Wang et al., 2012;
Kelkar & Reineke, 2011). These modalities provide targeted drug delivery to tumor
tissues and analyze the response generated by the released active moieties to the
desired organ or tissue while minimizing toxic effects (Sahoo et al., 2014). The
amalgamation of nanoparticles and theranostics is known to develop nanotheranos-
tics. These nanotheranostic tools are stratagem to extirpate cancer cells and simul-
taneously analyze the drug activity. The nanotheranostic agents consist of a
1 Targeted Nanotheranostic Systems in Cancer Therapy 3

therapeutic moiety such as nucleic acids (miRNA and siRNA), proteins, and target-
ing ligands that can be linked covalently or noncovalently to the delivery entity
(Nabil et al., 2019) (Fig. 1.1).
Nanotheranostics can be used in early-stage detection and treatments for patients
suffering from cancer. Multifunctional hybrid nanotheranostics help in treatment
planning, online tracking of therapeutic response, and further enabling personalized
medicine (Anselmo & Mitragotri, 2016). These nanotheranostics systems are used
for imaging, for instance, as optical guiding moieties during the surgical resection
of breast cancer and melanoma (Blau et al., 2018).
Many parameters such as particle size, loading capacity, and surface interactions
with the biological milieu are vital to be considered for any nanotheranostic design.
Nanoparticulate system with an optimal size between 5 nm and 200 nm is effective
for tumor targeting (Lammers et al., 2010). For instance, it was observed that
smaller-sized nanoparticles exhibit enhanced stability and extravasation to tumor
sites, whereas liposomes larger in size demonstrated better loading properties but
were unstable and easily approachable by the reticuloendothelial system and are
further cleared from blood circulation (Cruz et al., 2016; Perrie & Ramsay, 2017).
The size of nanoparticles also affects their interaction with biosurface, loading effi-
ciency, stability, and biodistribution index of the loaded drugs. The morphology,
surface charge, and composition of the nanoparticles have been different and can be
linked to different nanoparticles, i.e., stability, penetration inside the cells, and tox-
icity (Grumezescu, 2018).

Fig. 1.1 Scheme demonstrating nanotheranostic particles entering a cancer cell for therapeuti-
cally killing the cell. These particles further emit signs that can be analyzed utilizing a diagnos-
tic probe
4 A. Kour et al.

1.2.1 Different Types of Nanotheranostics

Nanoplatforms are the vital component of theranostic systems that act as a scaffold
to integrate imaging and therapeutic systems in single moiety and simultaneously
realize their activities. Various materials are used for the construction of nanother-
anostic scaffolds, and these are mentioned below (Fig. 1.2). Different applications
of these theranostic systems are further listed in Table 1.1

1.2.1.1 Magnetic Nanoparticles

Magnetic nanotheranostics have attained significant heed in the region of cancer

therapy. Magnetic nanoparticles facilitate MRI, positron emission tomography
(PET), optical imaging, and additionally promote effective delivery of gene(s) as
well as conventional chemotherapies. Magnetic nanoparticles also enable
hyperthermia-­based killing of cancerous cells. Magnetic nanoparticle-associated
hyperthermia produces local heat and thus results in the release of active moieties
either bound to the magnetic nanoparticles or encapsulated within polymeric matri-
ces (Kumar & Mohammad, 2011; Xie & Jon, 2012; Singh & Sahoo, 2014). These
theranostic agents are smaller in size, up to ~100 nm, allowing better penetration in
the tumor tissues and promoting enhanced delivery (Draz et al., 2014). Magnetic
nanoparticles particularly iron oxide nanoparticles (IONPS) can be surface func-
tionalized with chemotherapeutic agents, other targeting entities, and biocompatible
polymers due to their large surface area-to-volume ratio to reduce the cytotoxicity
of the nanoparticles (Xie et al., 2011; Yoo et al., 2013). To improve the multifunc-
tional capabilities of iron oxide nanoparticles, the biphasic system consisted of
PEGylated terbium along with the GdPO4 nanorice sensitized with cerium and

Fig. 1.2 Various types of cancer nanotheranostics

1 Targeted Nanotheranostic Systems in Cancer Therapy 5

Table 1.1 Type of cancer nanotheranostics and their applications

Nanotheranostic
agents Applications/advantages References
Magnetic Multimodal imaging Sahu et al. (2014)
Hyperthermia Kumar and Mohammad (2011); Xie
Methodical gene and drug delivery and Jon (2012); Singh and Sahoo
Thermal cell apoptosis (2014)
Enhanced cell penetration Patra et al. (2014)
Huang et al. (2015)
Yu et al. (2015)
Gold/silver Multimodal imaging Sahoo et al. (2014); Boisselier and
Easy to synthesize Astruc (2009)
Cell apoptosis by PTT and PDT Boisselier and Astruc (2009);
Natarajan et al. (2009)
Dixit et al. (2015); Liu et al.
(2015a); Shi et al. (2014);
Mukherjee et al. (2014)
Graphene Large surface area, colloidal stability Draz et al. (2014)
Image-assisted photothermal activity Miao et al. (2015b)
Super-paramagnetism, optical Shi et al. (2013)
absorbance
Silica Higher porosity Wang et al. (2015)
Image-assisted drug delivery Gao et al. (2013)
Lipid/polymeric Ease of fabrication Gu et al. (2007)
Longer duration of circulation Luk et al. (2012); Makino and
Higher specificity and low toxicity Kimura (2014)
Draz et al. (2014); Schroeder et al.
(2010)
Protein Enables both internal and external Lim et al. (2013)
surface modification Lim et al. (2013); Ren et al. (2014);
Ferritin nanocages have a natural Truffi et al. (2016); Wang et al.
affinity for human transferrin (2016)
receptor-1

glutamic acid. This biphasic system with the iron oxide nanoparticles exhibited
green light luminescence characteristics with efficient aqueous stability. This was
loaded with anticancer drug doxorubicin and demonstrated cell killing in vitro using
cell lines like HeLa and MCF-7. This multimodal system was considered as a pow-
erful tool for imaging and collaborative chemo-thermal cancer therapy (Sahu et al.,
2014). PEGylated molybdenum disulfide flakes amalgamated with iron oxide
nanoparticles have been utilized as a theranostic platform in vivo. These molybde-
num disulfide flakes carry photothermal properties to convert near-infrared light
into thermal and iron oxide magnetic characteristics, which were used to analyze
the transport of the particle to the tissue via an external magnetic field (Yu et al.,
2015). Superparamagnetic iron oxide nanotheranostics conjugated with the amphi-
philic poly(styrene)-b-poly(acrylic acid) doxorubicin and folic acid were used as
nanotheranostic component, and this nanoparticulate system was used for targeted
anticancer activity in human breast cancer and colon cancer cell line (Patra et al.,
6 A. Kour et al.

2014). SPIO nanotheranostic platform was fabricated and was further labelled with
the fluorescent dye 5-FAM and antibody HuCC49ΔCH2. Anticancer drugs such as
doxorubicin, azido-doxorubicin, MI-219, and 17-DMAG were encapsulated into
nanoparticles. pH-based release of the drug, distribution at the cellular level, and
cytotoxicity of the drug-loaded SPIO-nanotheranostic was analyzed utilizing fluo-
rescence microscopy and MTS assay. The structures exhibited enhanced targeting
and uptake in HuCC49ΔCH2-SPIO cells, as evidenced by various imaging tech-
niques (fluorescent imaging, MRI, and Prussian blue staining). It was observed that
HuCC49ΔCH2-SPIO nanotheranostics got accumulated in endosomes/lysosomes
where the encapsulated doxorubicin was released due to acidic environment persist-
ing in the lysosomes and from here further got diffused to the cytosol and nuclei. In
contrast, the encapsulated Adox demonstrated limited release in the endosomes/
lysosomes. Thus, HuCC49ΔCH2-SPIO-based nanotheranostics served as a plat-
form for cancer cell imaging and targeted anticancer therapy (Zou et al., 2010). The
anticancer activity of the well-known anticancer drug doxorubicin was also found
to increase when conjugated with the human serum albumin-templated iron oxide
nanoparticles. These nanotheranostic systems demonstrated anticancer potential in
4T1 cells when being analyzed via MRI (Quan et al., 2011). A triple modality
nanoparticle system composed of the iron oxide@Au nanostar (gold shell, Fe3O4
core) was used for the MRI, CT scanning, and thermal imaging of tumor cells
(Wang et al., 2005). Iron oxide cluster-structured nanoparticle platform templated
with hydrazine, ferrous chloride, and ligands have demonstrated photothermal
therapy-­based anticancer activity in HeLa cells and were monitored utilizing optical
coherence tomography microscopy (OCTM) (Huang et al., 2015). These nanostruc-
tures were claimed for the imaging and exhibited enhanced therapeutic efficacy than
cetuximab only, in A431 and 32D/EGFR overexpressed epidermal growth factor
receptor (EGFR) cell lines (Tseng et al., 2015) (Fig. 1.3).

1.2.1.2 Gold- and Silver-Based Nanotheranostics

Apart from iron, many other nanoparticles, composed of gold and silver, can be eas-
ily fabricated with various surface modifications, more biocompatible, and less
cytotoxic (Boisselier & Astruc, 2009). Gold nanoparticle conjugated with
microRNA, quantum dots, and streptavidin/biotin adhered with a chimeric mouse-­
human IgG1 monoclonal antibody (mAb) ChL6 (MAb-ChL6) were developed for
the therapy of the breast cancer. This system inhibited breast cancer by inhibiting
proliferation of the cell and thus leading to the apoptosis with no effect on normal
cells and was analyzed using microscopic techniques (Natarajan et al., 2009). Gold
nanobeacons conjugated with the 30-Cy3 and 50-thiol-C6 were used for mRNA
silencing in HCT 116 cells (Conde et al., 2013). Fluorescent gold nanoclusters
encapsulated with suicidal gene CD_UPRT (cytosine deaminase-uracil phosphori-
bosyltransferase) and prodrug 5-fluorocytosine were used for the targeted inhibition
of the HeLa cells (Sahoo et al., 2014). Nanosystems comprising the gold nanopar-
ticles with the biodegradable liposomes have shown therapeutic effect via
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