Drug Delivery

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Metal nanoparticles as a promising technology in

targeted cancer treatment

Jia-Jie Xu, Wan-Chen Zhang, Ya-Wen Guo, Xiao-Yi Chen & You-Ni Zhang

To cite this article: Jia-Jie Xu, Wan-Chen Zhang, Ya-Wen Guo, Xiao-Yi Chen & You-Ni Zhang
(2022) Metal nanoparticles as a promising technology in targeted cancer treatment, Drug
Delivery, 29:1, 664-678, DOI: 10.1080/10717544.2022.2039804

To link to this article: https://doi.org/10.1080/10717544.2022.2039804

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DRUG DELIVERY
2022, VOL. 29, NO. 1, 664–678
https://doi.org/10.1080/10717544.2022.2039804

RESEARCH ARTICLE

Metal nanoparticles as a promising technology in targeted cancer treatment

Jia-Jie Xua,b, Wan-Chen Zhanga,b,c, Ya-Wen Guoa,b, Xiao-Yi Chend and You-Ni Zhange
a
Department of Head and Neck Surgery, Otolaryngology & Head and Neck Center, Cancer Center, Zhejiang Provincial People’s Hospital
(Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China; bKey Laboratory of Endocrine Gland Diseases of Zhejiang
Province, Hangzhou, China; cSecond Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China; dClinical Research
Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, China; eDepartment of
Laboratory Medicine, Tiantai People’s Hospital of Zhejiang Province (Tiantai Branch of Zhejiang People’s Hospital), Taizhou, China

ABSTRACT ARTICLE HISTORY

Traditional anticancer treatments have several limitations, but cancer is still one of the deadliest dis- Received 12 December 2021
eases. As a result, new anticancer drugs are required for the treatment of cancer. The use of metal Revised 31 January 2022
nanoparticles (NPs) as alternative chemotherapeutic drugs is on the rise in cancer research. Metal NPs Accepted 1 February 2022
have the potential for use in a wide range of applications. Natural or surface-induced anticancer
KEYWORDS
effects can be found in metals. The focus of this review is on the therapeutic potential of metal-based Cancer treatment; metal
NPs. The potential of various types of metal NPs for tumor targeting will be discussed for cancer treat- nanoparticles; targeting;
ment. The in vivo application of metal NPs for solid tumors will be reviewed. Risk factors involved in radiation therapy;
the clinical application of metal NPs will also be summarized. hyperthermia

1. Introduction million deaths in 2020. A statistical overview of newly

reported cancer cases and deaths reported are presented in
Cancer is a condition in which abnormalities in the genome
Figure 1 (Cancer, 2022).
arise. These changes trigger unregulated cell division, result-
The most prevalent cancer therapies are chemotherapy,
ing in tissue damage (Pugazhendhi et al., 2018). Cancer is a
multifactorial disease because of its complex combination of radiation, and surgery (Singhal et al., 2010). One of the most
hereditary and environmental components. DNA damage is frequent cancer treatments is chemotherapy. Conventional
the primary cause of the abnormalities responsible for cancer chemotherapy mainly kills cancer cells by blocking mitosis
(Rivas-Dom
ınguez et al., 2021). Cancer has the highest clin- and preventing DNA synthesis. Unintended and sometimes
ical, social, and economic burden of any human disease in fatal side effects may occur when chemotherapeutic drugs
terms of cause-specific disability-adjusted life years (DALYs). target healthy tissues, particularly those that are rapidly
The overall risk of developing cancer for people aged expanding like blood and digestive tract cell membranes
0–74 years is 20.2% (22.4% in men and 18.2% in women, (Hossen et al., 2019). Traditional chemotherapy must be sup-
respectively) (Mattiuzzi & Lippi, 2019). Sung et al. reported plemented or replaced with less harmful systems due to the
alarming global cancer statistics for the year 2020. Globally, harm that conventional chemotherapeutic agents cause to
an estimated 19.3 million new cancer cases (18.1 million healthy cells (Yan et al., 2020). Similarly, radiotherapy has
excluding nonmelanoma skin cancer) and almost 10.0 million many disadvantages as the radiations are also delivered to
cancer deaths (9.9 million excluding nonmelanoma skin can-
the healthy tissues surrounding the tumor and have the
cer) occurred in 2020. As the most diagnosed cancer, female
potential to harm them (Çeşmeli & Avci, 2019). Surgical ther-
breast cancer exceeded lung cancer. Breast cancer had 2.3
apy is not only costly but also a very complicated procedure.
million new cases (11.7%), followed by lung (11.4%), colorec-
It requires specific expertise as well. Surgical therapy may
tal (10.0%), prostate (7.3%), and stomach (5.6%) cancers.
Lung cancer remained the leading cause of cancer death, also necessitate additional clinic visits due to suture removal,
with an estimated 1.8 million deaths (18%), followed by colo- infection, contact dermatitis, spitting sutures, and graft
rectal (9.4%), liver (8.3%), stomach (7.7%), and female breast check, among other things. Furthermore, many elderly
(6.9%) cancers (Sung et al., 2021). According to a report by patients require additional care after surgery, such as dress-
the World Health Organization (WHO), cancer was the pri- ing changes, transportation, and follow-up visits, which adds
mary cause of mortality worldwide, contributing to about 10 to the cost of surgical therapy (Ahluwalia et al., 2020).

CONTACT Xiao-Yi Chen [email protected] Clinical Research Institute, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou
Medical College), No. 158 Shangtang Road, Hangzhou 310014, Zhejiang Province, China; You-Ni Zhang [email protected] Department of
Laboratory Medicine, Tiantai People’s Hospital of Zhejiang Province (Tiantai Branch of Zhejiang People’s Hospital), No. 1 Kangning Middle Road, Shifeng Street,
Tiantai County, Taizhou 317200, Zhejiang Province, China
ß 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
 DRUG DELIVERY 665

Figure 1. Statistics on the deaths due to cancer and newly reported cancer cases in the year 2020. MM: millions of people.

Nanotechnology has opened a new era in every field of In this review, the role of metal NPs in cancer therapy will
life. The timeline of the advancement in nanotechnology has be discussed. It will be examined how metal NPs reach the
been represented in Figure 2. The ability of nanotechnology target areas by exploiting either the leaky vasculature within
to detect a wide range of molecular signals and biomarkers the tumor or targeting the overexpressed receptors on the
in real-time is just what drives breakthroughs in early detec- tumor cells. The purpose of this article is to enlighten
tion, diagnostics, prognostics, and therapeutic strategy. researchers, particularly those working on nanotechnology-
Cancer nanotherapeutics have overcome several shortcom- based cancer therapy, about the potential of metal NPs in
ings of conventional therapies, including nonspecific biodis- cancer treatment. The advantages of noble and non-noble
tribution, low water solubility, and poor bioavailability. It metals and their drawbacks will be highlighted. The clinical
provides high sensitivity, specificity, and multiplexed meas- potential of metal NPs will be determined by their efficacy
urement capacity (Zhang et al., 2019). A nanoparticle (NP) is against cancer cell lines and in vivo tumors. The last part will
a particle that has dimensions between 1 and 100 nm. When deliberate the toxicity concerns of the metal NPs in clinical
compared to the traditional drug delivery systems, NP-based application.
drug delivery systems have higher efficacy due to increased
half-life of vulnerable drugs and proteins, improved solubility
2. Mechanism of cancer-targeting
of hydrophobic drugs, and the ability to control and target
drug release in diseased sites (Dang & Guan, 2020). The Metal NPs have been reported to have antitumor properties.
types and characteristics of NPs based on size (1–100 nm), The mechanisms of action involved in cancer therapeutics
type (metal or polymeric), shape, and targeting are depicted have been discussed below. Figure 5 illustrates these
in Figure 3. mechanisms.
Metal NPs have gained specific attention among all the
NPs because these have the potential to serve as multipur-
2.1. Active or passive targeting of tumor
pose agents. Gold, silver, iron and/or iron oxide, zinc, titan-
ium, cerium oxide, nickel, copper, magnesium, barium, Therapeutic agent accumulation can be enhanced by metal
calcium, and bismuth-based metal NPs have been reported NP treatments in two ways: passive and active. For cancer
as a cancer treatment. The leading role of metal NPs in the treatment, abnormal branching and leaky sites with pore
current research platforms against cancer, and the research sizes ranging from 100 nm to several hundred nanometers
interest in this topic is increasing day by day, as can be are commonly found in tumor vasculatures. The reason is
depicted in Figure 4. The comparison of five commonly syn- the rapid development of endothelial cells reduced the num-
thesized metal NPs showed that gold NPs are among the ber of pericytes (Lok et al., 2014). Due to this leaky vascula-
leading, followed by silver and magnetic nanoparticles ture, the body concentrates inert metal NPs in the tumor
(MNPs). Several studies have shown metal NPs can be used under the passive targeting mechanism. This is referred to as
to treat cancer and preliminary and clinical trials are now the increased permeability and retention (EPR) effect. On the
underway. The non-noble metal-based cancer therapy can other hand, active targeting enhances the therapeutic deliv-
progress toward cost-effective treatment as compared to ery system by functionally modifying the metal NP’s surface,
expensive chemotherapy. resulting in selective tissue targeting (Pissuwan et al., 2006).
666 J.-J. XU ET AL.

Figure 2. Timeline of the advancement in nanotechnology.

The surface modification of NPs with tumor-targeting ligands silver NPs, with a diameter of 13 nm, was used to functional-
such as antibodies, folic acid, and peptides, or the incorpor- ize the hybrid peptide–metal NPs biointerface. Cellular
ation of tumor-targeting ligands into NPs via disulfide bond- uptake by SH-SY5Y neuroblastoma and K562 chronic myelog-
ing, might result in targeted intra-tumor drug release (Wang enous leukemia cells was confirmed by confocal microscope
et al., 2012). In a study, silver NPs functionalized with a fluor- imaging (Di Pietro et al., 2016).
escent cyclic arginine–glycine–aspartic acid (RGD) peptide
were found to be effective in identifying and targeting can-
cerous cells. Researchers found that the RGD peptide
2.2. Tumor targeting through gene silencing
sequence can interact specifically with integrins, which are
critical receptors for cancer growth and bacterial adhesion/ The regulation of gene expression in a cell to prohibit the
invasion. Immobilization of a fluorescent RGD peptide onto expression of a specific gene is known as gene silencing.
 DRUG DELIVERY 667

Figure 3. NPs categorized based on their size, material, surface, and shape.

Figure 5. Mechanisms involved in cancer targeting.

Figure 4. Number of publications for the year 2001–2021. Data retrieved from
sciencedirect.com with search terms ‘metal’, or respective ‘metal name’, be delivered to cells by using a platelet cell membrane-
‘nanoparticle’, and ‘cancer’ on January 22 2022. coated metal (zinc)-organic framework (MOF). Using a simple
one-pot method, synthetic siRNAs were loaded onto porous
Due to its potential to suppress genes implicated in tumor metal-organic framework (MOF) NPs. pH affects the structural
formation, gene silencing grasps promising cancer therapy integrity of MOF scaffolds. In vitro targeting and intracellular
gene silencing is the process of altering gene expression on localization were performed on human SK-BR-3 breast cancer
an epigenetic level. This is accomplished mostly through the cells (HTB-30; American Type Culture Collection, Manassas,
use of antisense DNA and short interfering RNA (Liu et al., VA). To bind specifically to cancer cells, a platelet membrane
2019). Fernandes & Baptista (2017) reported gene silencing coating was employed (Fernandes & Baptista, 2017).
using multifunctional gold NPs for cancer therapy to improve
tumor cell identification and uptake. Gold NPs’ surfaces were
functionalized using targeting peptides. This approach inhib-
2.3. Drug delivery through nanoparticles
its KRAS gene expression in colorectal cancer cell lines while
leaving healthy fibroblasts unharmed. Gene silencing with Cancer drugs in clinical practice are low molecular weight
small interfering RNA (siRNA) is another option. siRNAs can chemicals that can diffuse easily into healthy tissues as well
668 J.-J. XU ET AL.

Table 1. Comparison of IC50 values of the anticancer drugs-based metal nanoparticles and their comparison with the free drug.
IC50 value of Anticancer IC50 value of
Nanoparticle type Cancer cell line nanoparticle system drug free drug References
Resveratrol stabilized gold Glioma carcinoma cell 4 lg/mL Doxorubicin 6 lg/mL Mohanty
nanoparticles line (LN 229) et al. (2014)
Multifunctional nanosystem HeLa cancer cells 2.3 lg/mL Doxorubicin 0.5 lg/mL Pan et al. (2017)
(MFNCs) of gold nanorods, iron
oxide nanoparticles, and gold
nanoclusters assemblies within
BSA nanoparticles
Gold nanoparticles based Lung cancer cell 25 mM Docetaxel 38 mM Thambiraj
nanoconjugates line (H520) et al. (2019)
Gold nanoparticles Breast cancer cells 30 ± 5 lg/mL Chloroquine >30 ± 5 lg/mL Joshi et al.
MCF-7 (2012)
Silver nanoparticle HepG2 cells 1.92 lg/mL Epirubicin 0.11 lg/mL Ding et al. (2019)
Jacalin-capped silver nanoparticles Human chronic 100 nM Acetylshikonin (AS) and beta- 500 nM Ayaz Ahmed
myeloid leukemia dimethylacrylshikonin et al. (2016)
(BDS)
PEG capped silver nanoparticles Breast cancer cells 258.6 lg/mL Methotrexate 512.7 lg/mL Muhammad
MCF-7 et al. (2016)
Copper nanoparticles Drug-resistant prostate 85, 172, and 193 nM Paclitaxel (control) 2575 nM Chen et al.
based systems cancer cell (2018)

as tumor tissues. This results in an even distribution through- cancer treatment in which bodily tissue is subjected to high
out the body, a short half-life, and a rapid clearance rate. temperatures, usually up to 113 degrees Fahrenheit
The amount of medicine that reaches the target site is very (40–45
C), in order to harm or kill cancer cells (Jose et al.,
low, lowers therapeutic efficacy, and increases the risk of 2020). All hyperthermia-related events aim to change the
side effects, including the possibility of drug resistance extracellular milieu by triggering immune responses and
(Skoetz et al., 2017; Farzin et al., 2020). Metal NPs can act as driving tumor cells to switch to an anaerobic metabolic sys-
vectors for targeted drug delivery. Both hydrophobic drugs, tem (Balivada et al., 2010). Hyperthermia is divided into three
e.g. paclitaxel loaded selenium NPs (Bidkar et al., 2017) and categories based on the site of application: whole-body
hydrophilic drugs, e.g. doxorubicin (DOX) loaded iron oxide hyperthermia, regional hyperthermia, and localized hyper-
(Fe3O4@SiO2@mSiO2) NP drug delivery system (Gao et al., thermia. Depending on the form of application, whole-body
2018) can be loaded into metal NPs. The small size and sta- hyperthermia can be invasive or noninvasive. Invasive hyper-
bility of the metal NPs enhance the bioavailability of the thermia is the process of heating blood extracorporeally,
drugs. Metal NP formulation containing a superparamagnetic whereas noninvasive hyperthermia is the process of increas-
iron oxide core coated with short- and long-chain polyethyl- ing temperature through the use of hot air, hot wax, or RF
ene glycol (PEG) was reported. The hydrophobic paclitaxel or IR irradiation, which cannot be used to treat deep tumors
and folic acid were coupled to a metallic core, and the PEG (Wust et al., 2002). Hyperthermia in a specific area called
served as a hydrophilic outer layer. When compared to free regional hyperthermia uses noninvasive treatment (e.g. non-
paclitaxel, the NPs system delivered the drug at conditions ionizing electromagnetic radiation (NIR) or ultrasound are
that mimicked the acidic intracellular pH of breast cancer used to heat regionally situated tumors) or invasive
cells, and the folic conjugation resulted in higher NP absorp- approaches (e.g. thermal conduction, or the use of magnetic
tion by target cells, which increased the cytotoxicity to target implants) (Baker et al., 1982; Longo et al., 2016). The invasive
cells (Jeon et al., 2019). In another study, for colon target or noninvasive procedures listed above are utilized to heat
dual drug delivery, a chitosan/palladium nanocomposite was tiny tumors to a depth of 4 cm in the localized hyperthermia
created. Curcumin (CUR) and 5-fluorouracil (5-FU) were approach (Jose et al., 2020). Nanotechnology especially MNPs
loaded individually and in combination with chitosan/Pd has created a huge opportunity to advance the field of
nanocomposite. The growth of HT-29 cells is inhibited more hyperthermia. The heat dissipation processes of MNPs can be
effectively by co-encapsulated nanocomposite than by 5-FU, used to understand the mechanism of tumor-killing by
CUR monotherapy (Dhanavel et al., 2017). Some NP systems hyperthermia. Magnetic NPs disperse heat to tumor cells
have higher IC50 values as compared to the free drug through two processes: Neel relaxation and Brownian relax-
because of slow drug release, but the systems show suffi- ation. Neel relaxation occurs when the magnetic moment
cient credibility as targeted drug delivery systems (Pan et al., reorients parallel to the applied magnetic field, whereas
2017). The comparison of IC50 values of the anticancer drugs- Brownian relaxation happens when the nanomaterial is
based metal NPs and their comparison with the free drug is mechanically rotated toward the external magnetic field.
given in Table 1. When a material is exposed to an external alternative mag-
netic field (AMF) with a magnetic field reversal time less than
the material’s magnetic relaxation period, both processes
2.4. Nanoparticles based hyperthermia
occur (Chen et al., 2017). High-grade superparamagnetic
When biological materials are heated just a few degrees MnFe2O4 NPs were manufactured using a low-cost and envir-
beyond their normal temperature, significant changes occur, onmentally friendly co-precipitation approach with the goal
including ceil death. Hyperthermia therapy is a type of of hyperthermia application. The results showed that
 DRUG DELIVERY 669

MnFe2O4 MNPs could reach hyperthermia temperature appears perfect, but hyperthermia prior to radiations is
(42
C) in 260 seconds at a low level of 0.4 g/mL, indicating thought to be more successful. Inverse Metal NPs improve
that the material could be employed as a heating agent in radiation targeting while also causing a hyperthermic
magnetic hyperthermic treatment (Patade et al., 2020). Ma response at the tumor location. When heat is combined with
et al. reported Fe3O4–Pd Janus NPs with amplified dual- metal and RT for cancer, response rates increase by 16–26%
mode hyperthermia and enhanced ROS generation for breast (CeR drowska et al., 2020; Tolkaeva et al., 2021).
cancer treatment. Under alternating magnetic field (AMF) Sears et al. have shown that triple-negative breast cancer
plus laser irradiation, Fe3O4–Pd JNPs achieved a larger tem- is sensitive to photothermal and ionizing radiation.
perature enhancement than the corresponding individual Nanoparticles of silver having a peak absorbance in the near-
modality (only AMF or laser irradiation alone for Fe3O4–Pd infrared (NIR) spectrum were produced. The scientists tested
JNPs) or the total of two individual modalities. In the pres- the possibility of treating MDA-MB-231 TNBC cells selectively
ence of H2O2 in an acidic environment, Fe3O4–Pd JNPs without harming nonmalignant MCF-10A breast cells using a
increased ROS generation due to the interface synergistic multimodal method based on combination photothermal
effect in creating hydroxyl radicals (OH), which was realized therapy, IR sensitization, and targeted cytotoxicity. There
by Fe3O4 NP-based Fenton reaction and Pd nanosheet-based were no nonmalignant mammary epithelial cells saved as a
catalytic capabilities. Surprisingly, with external AMF þ laser result of this combination. It was shown that thermal radi-
irradiation, the ROS level was raised even higher. On an ation sensitization using triangular silver NPs resulted in
orthotopic mouse breast cancer model, the anti-tumor activ- excellent results despite the lower treatment dose and fre-
ity of Fe3O4–Pd JNPs was tested in vivo. Under AMF with quency (Sears et al., 2021), excellent results despite the lower
laser irradiation, guided by MRI/PA dual-mode imaging with treatment dose and frequency (Sears et al., 2021). When
excellent spatial resolution and precision, Fe3O4–Pd JNPs pro- combined with the histone deacetylase inhibitor SAHA, gold
vided full tumor suppression without notable deleterious NPs and radio sensitization were tested in 2D and 3D cancer
effects (Ma et al., 2019). cell cultures. Radiation-resistant A549 and DU-145 cancer
cells were used to test the treatment’s effectiveness. Prior to
radiotherapy, gold NPs and SAHA dramatically reduced the
2.5. Radiotherapy treatment through nanoparticles
number of live cells, which indicates that the combination of
High-energy radiations are used in radiation therapy (RT) to gold NPs and SAHA significantly boosted the potency of
inhibit the proliferation or kill malignant cells. Ionizing radia- irradiation (Igaz et al., 2020).
tions are the type of primary concern for cancer treatment.
Ionizing radiation is electromagnetic radiation with sufficient
energy to ionize or remove electrons from atoms or mole- 3. Metal nanoparticles used for cancer therapy
cules, resulting in the formation of ions. Ions with high kin- Various metal NPs have been employed in cancer treatment.
etic energy collide several times, depositing a considerable The metal NPs can be divided into noble and non-noble
amount of energy in the cells they travel through. The trans- metals-based NPs. The role of some of the metal NPs in can-
ferred energy is sufficient to stop tumor cells from replicating cer treatment is highlighted in Table 2.
DNA or transcribing RNA, resulting in cell death. The most
difficult aspect of radiotherapy is delivering a deadly dosage
of radiation to tumor cells while preventing unintended cell 3.1. Noble metals-based nanoparticles for cancer
damage (Fard et al., 2017; Song et al. 2017; C
esaire et al. therapeutics
2018; Richardson et al., 2018; Carozza et al. 2020). Metal NPs The noble metal is the metal from any of the several metallic
are widely employed in radiotherapy to increase the specifi- chemical elements that have outstanding oxidation resist-
city of radiations to the targeted spot, reducing radiation ance, even at high temperatures. The main limitation with
dose and preventing toxicity and injury to normal tissues. their application is the high cost of these metals. Noble met-
Ionizing radiation causes the radiolysis of water molecules, als commonly employed for NPs preparation include gold,
resulting in the production of reactive oxygen species (ROS). silver, platinum, and palladium.
They have a significant damaging effect on DNA due to the
unpaired electron. Metal NPs use a variety of ways to
improve radiation targeting. Metals increase tumor cell oxida- 3.1.1. Gold nanoparticles
tive stress, promote selective apoptosis, and reduce clono- The non-reactive nature of gold makes it a noble element.
genic survival (Al-Musywel & Laref 2017; Choi et al., 2020; Its resistance to chemical oxidation renders it impervious to
Igaz et al., 2020; Schuemann et al., 2020). Various metal NPs degradation and corrosion. Thus, it can retain its form and
have been used in recent RT research; however, silver and luster for millennia. Gold NPs can be made in a variety of
gold NPs surpass other metal NPs for radio sensitization ways, including chemical, physical, biological, and green syn-
applications in cancer imaging and therapy due to their high thesis. The bottom-up and top-down approaches are used in
atomic number and mass-energy coefficient. To cope with all types. Gold NPs have a wide variety of biomedical appli-
cancer, a synergistic treatment of ionization and hyperther- cations due to their unique physicochemical characteristics
mia is also effective. Simultaneous treatment that causes (Chen et al., 2013). Recently, there has been a lot of discus-
hyperthermia in tumor cells while also delivering radiations sion about tumor targeting. Gold-based metal NPs system
670 J.-J. XU ET AL.

Table 2. Potential of metal nanoparticles as cancer treatment.

Type of metal nanoparticles Targeted cancer Targeting role References
Glyco-gold nanoparticles Cervical cancer (HeLa and L929 cells) Conjugated RNase Zhao et al. (2021)
Silver nanoparticles Pancreatic cancer (PANC-1, AsPC-1, Oxygen based (ROS) or nitrogen Wang et al. (2021)
and MIA PaCa-2 cells) based (RNS) reactive species
Mesoporous platinum nanoparticles Breast cancer (MCF-7/ADR cells) Photothermal therapy/doxorubicin Fu et al. (2020)
Superparamagnetic iron oxide Breast cancer bone metastasis (MDA- Bone-targeting peptide-conjugated Pang et al. (2021)
nanoparticles MB-231/ bone marrow cells)
Nickel oxide nanoparticles Triple-negative breast cancer cells Folic acid decorated and pH-sensitive Binu et al. (2021)
(Vero cell line and MDA-MB-
231 cells)

Figure 6. Gold nanoparticles physicochemical properties and functionalization against cancer.

along with their cancer-targeting properties have been ela- 3.1.2. Silver nanoparticles
borated in Figure 6. The anti-tumor effects of gold NPs can Silver NPs are becoming increasingly popular in biomedicine
be further enhanced by surface functionalization or coating, due to the wide range of applications they have, such as
and these NPs can be used for a variety of diagnostic, thera- antimicrobial wound dressings, topical lotions to prevent
peutic, bioimaging, and prognostic purposes. infection, and anticancer therapies (Sondi & Salopek-Sondi,
Botteon et al. reported the biosynthesis of gold NPs and 2004). The primary mechanisms through which silver NPs
used a bee product called Brazilian red propolis (BRP). T24 function include ROS, oxidative stress, and DNA damage.
bladder cancer and PC-3 prostate cancer cell lines were ROS are essential for the survival of cells since they help to
treated with biosynthetic gold NPs and exhibited substantial keep their internal balance in check. As a byproduct of cellu-
in vitro cytotoxic effects (Bray et al., 2018). Curcumin and iso- lar metabolism, ROS is a key player in signaling networks
nicotinic acid hydrazide corona functionalized gold NPs were within cells. However, an excessive amount of intracellular
formulated to target cancer, according to Umapathi et al. ROS damages DNA, lipids, and proteins as a mechanism for
(2020). Lung cancer cells (LK-2) and fibrillary epithelial cells silver NP-induced toxicity (Jain et al., 2021). Toxicity in
(TIG-120) are particularly sensitive to the harmful effects of treated cells is caused by the release of silver ions in the
functional NPs. The generation of ROS by conjugating CUR cytosol following endocytosis of silver NPs and their break-
and INH on AuNPs increased anticancer activity (ROS). When down in an acidic environment. Thus, silver NPs have been
the investigation was extended, apoptosis and morphological linked to an increased risk of cancer and cell death due to
changes in LK-2 and TIG-120 cells were identified. their ability to interfere with the cell’s basic metabolic and
Additionally, the anticancer efficacy of these NPs is con- cell cycle pathways (De Matteis et al., 2015). Silver NPs func-
trasted with that of traditional cisplatin (Botteon et al., 2021). tionalized paclitaxel nanocrystals boost the overall anti-
 DRUG DELIVERY 671

cancer activity on human cancer cells, according to functionalization. This strategy improved anticancer efficacy
Muhammad et al. (2021). Nanocrystals were developed that by dismantling the established coordination interactions
combined the organic anti-cancer drug paclitaxel with inor- between the host and guest species (Dhavale et al., 2021).
ganic silver NPs as tumor-targeting agents. The polydop- The technique considerably aided tumor eradication by facili-
amine (PDA) was applied to the paclitaxel nanocrystals, tating deep tumor penetration and simultaneously generat-
which were used as a template. Silver NPs and the tumor-tar- ing detrimental free radicals for the destruction of MDR
geting peptide NR1 were grafted onto the PDA layer, which malignancies (Kankala et al., 2020).
was also a connecting bridge for manufacturing and deposit-
ing the silver NPs in situ (RGDARF). Drug nanocrystals coated
with NR1/AgNP demonstrated dramatically improved cellular 3.1.4. Palladium nanoparticles
absorption efficiency, in vitro anti-cancer activity and an anti- Palladium NPs can be used in theragnostic applications
migration effect against a range of cancer cells as a result. because of their outstanding catalytic and optical capabil-
According to the data, silver NPs and paclitaxel had an addi- ities. Palladium nanomaterial has been used as a prodrug
tive or synergistic influence on each other, as well as on the activator, photothermal agent, and anticancer and/or anti-
NR1-receptor interaction, pH-responsive drug release, and bacterial therapy, according to researchers. The multifunc-
the small size. In terms of selectivity and biocompatibility, tional palladium NPs mediating photothermal therapy along
these NR1-AgNP-decorated PTX nanocrystals were very well- with imaging have been presented in Figure 7.
balanced. The apoptotic efficacy of these nanocrystals was It has been claimed that palladium NPs can be biosynthe-
also high, resulting in lysis of the cell membrane as well as sized cost-effectively utilizing Saudi propolis. With an IC50 of
damage to the nucleus, dysfunction of the mitochondria, 104.79 mg/mL, palladium NPs successfully cured MCF-7 ductal
excessive production of ROS, and double-stranded DNA cancer (Al-Fakeh et al., 2021). These palladium NPs have
breakage. Authors proposed that P53 and caspase 3 activa- been modified to treat MCF7 breast cancer cells using PVP-
tion, as well as Bax-to-Bcl-2 ratio modification, may be rele- functionalized palladium. PVP-palladium NPs dramatically
vant to the putative acting mechanism and molecular basis reduced the viability of human breast cancer MCF7 cells at
of these distinct pharmacological nanocrystals (Umapathi increasing doses. Caspase3/7 enzymatic activity was hypothe-
et al., 2020; Muhammad et al., 2021). sized to be the mechanism for the system’s induction of
death by causing damage to mitochondrial membrane
potential and nuclear DNA (Ramalingam et al., 2020).
3.1.3. Platinum nanoparticles
Patients are treated all around the world using platinum-
based drugs like cisplatin, carboplatin, and oxaliplatin. 3.2. Non-noble metals-based nanoparticles for cancer
However, the lack of specificity in cancer treatment leads to therapeutics
adverse effects and an increase in drug resistance (Mochida Non-noble metals despite their prone nature to oxidation
et al., 2017). Biotechnology, nanomedicine, and pharmacol- have many advantages like they are low cost, abundant, and
ogy all use platinum NPs in respective studies. Inorganic plat- possess good conductivity. The application of these metals
inum NP nanoformulations are yet to be tested in humans. in cancer therapeutics is described below.
The longer the platinum NPs can circulate inside the body,
the more beneficial it may be to coat their surfaces with a
biocompatible substance like polyvinylpyrrolidone (PVP) 3.2.1. Magnetic nanoparticles (iron/nickel)
(Jeyaraj et al., 2019). In a study, DOX was used as a model The manipulation of MNPs is possible due to the use of
drug, to make PVP-functionalized platinum NPs with an octo- external magnetic fields. Magnetic materials such as iron,
pod shape that demonstrated mono-dispersity. The system nickel, or cobalt and functional chemicals are the most com-
was used to improve drug distribution and reduce toxicity. It mon components of these particles (Edis et al., 2021). A
was found that both drug release and biocompatibility were high-frequency magnetic field can elevate the temperature
improved with the platinum–DOX conjugate system. Two of the tumor to 40–46
C by generating heat from these NPs.
intrinsic breast cancer cell subtypes (MCF-7 and MDA-MB- Another noteworthy potential of MNPs is their ability to
231) were used to assess the system’s cytotoxic capacity. The combine heat (hyperthermia) with drug release in cancer
mechanisms involved in inhibiting the PI3K/AKT signaling treatment (Dwivedi et al., 2020). In a study, MNPs containing
pathway via activation of the tumor suppressor gene PTEN DOX–gelatin cores and Fe3O4–alginate shells were used to
were found to be implicated (Patel et al., 2021). Kankala deliver targeted anticancer drugs. Doxorubicin was used as a
et al. postulated that platinum NPs can penetrate deep into model drug and implanted in the gelatin core to achieve
tumors and have synergistic therapeutic effects because of excellent encapsulation efficiency. Controlled drug release
the free radical species-assisted catalysis of platinum NPs. was achieved by using an outer magnetic film, which could
The ultrasmall platinum NPs were disseminated in chitosan target the tumor tissue. These NPs were observed in the
loaded across zinc-doped mesoporous silica nanocarriers nucleus of MCF-7 breast cancer cells with an external mag-
through a self-assembly mechanism. Doxorubicin molecules netic field. Using an external magnetic field, the NPs effi-
were loaded more efficiently into the tumor’s acidic micro- ciently targeted MCF-7 breast cancer cells, and after six
environment by the zinc species doped in the siliceous hours of incubation, they appeared in the nuclei of those
frameworks, without the need for any additional cells. MCF-7 cell viability declined to 52.3% after 12 hours of
672 J.-J. XU ET AL.

Figure 7. Preparation (A), functionalization and tumor targeting (B) of palladium nanoparticles (Bharathiraja et al., 2017).

treatment, with relative fluorescence intensity of 98.4% recently because of their ability to produce ROS when
(Huang et al., 2020). Anticancer drug telmisartan (TEL) was exposed to light. Particles of zinc oxide can be modified
delivered to Fe3O4 magnetic nanoparticles (MNPs) via grafted chemically to increase their photocatalytic efficiency as well
chitosan, a naturally occurring hydrophilic and biodegradable as their ability to generate ROS by a variety of methods
polymer. Drug-loaded MNP-CS (MNP–CS–TEL) exhibited pH- including doping with metals, polymer modification, and
responsive controlled release properties. The cytotoxicity of organic photosensitizing agents. The improved antibacterial
MNP–CS–TEL against PC-3 human prostate cancer cells was and anticancer activity of modified zinc oxide NPs can be
dose-dependent. The anticancer effects of the anticipated attributed to their increased ROS generation efficiency
nano-formulation were found to be significant (Dhavale (Sivakumar et al., 2018). The potential anticancer activity of
et al., 2021). The capacity to load large amounts of pharma- the CUR-loaded zinc oxide NPs was investigated using the
ceuticals and control drug release are two advantages of MTT assay on the rhabdomyosarcoma RD cell line, while their
adding MNPs into self-assembled hybrid NPs. In this context, cytotoxic effects were assessed using the resazurin assay on
NPs made of nickel ferrite (NFO) have been used to deliver human embryonic kidney cells. The large aspect ratio of ZnO
anti-cancer drugs. Poly vinyl alcohol/stearic acid hybrid with structures was considered a factor in the NPs’ increased cyto-
NFO-containing PEG was used for zidovudine (AZT) distribu- toxicity (Perera et al., 2020). In another study, it was reported
tion. AZT was intracellular delivery confirmed via NFO-rein- that egg albumin was used in the biosynthesis of zinc oxide
forced hybrid NPs (Joshy et al., 2020). An emphasis is also NPs. The system showed anticancer efficacy on MCF-7 as
placed on the green chemistry-based fabrication of MNPs.
measured by the MTT assay, with considerable cytotoxicity
The green synthesis of nickel oxide NPs in Arabic gum was
and correspondingly reduced cellular viability. The prepared
reported. To test the cytotoxicity of nickel oxide NPs, they
NPs induced ROS, which increased the regulated transcrip-
used the MTT method on cancer U87MG cell lines. For
tion of mRNA levels of apoptotic genes such as p53, bcl-2,
U87MG cancer cells, the IC50 of this compound was
caspase-3, and caspase-9 while drastically downregulating
37.84 g mL (Sabouri et al., 2021).
the expression of anti-apoptotic gene Bcl-2, according to a
gene expression research (RT-PCR) and western blot analysis.
3.2.2. Zinc oxide nanoparticles The findings suggested that the nano system specifically sup-
One of the most common metallic NPs in the world is zinc pressed MCF-7 gene expression via ROS damage and cell
oxide. Zinc oxide NPs have received a lot of attention death induced by cytotoxicity (Vijayakumar et al., 2020).
 DRUG DELIVERY 673

3.2.3. Copper nanoparticles decreased significantly compared to the mice receiving laser
Copper is a necessary component of plant and animal therapy alone (Behnam et al., 2018).
metabolism. Naturally, it is a soft, moldable, and easy to
bend substance, with high thermal and electrical conductiv-
3.2.6. Magnesium nanoparticles
ities. When compared to analogous other metals, such as
Superparamagnetic magnesium ferrite-based NPs are used as
platinum, silver, and gold, copper NPs are cheaper among
radiosensitizers. Bio-nanocomposites and NPs systems have
the transition metals under consideration (Rayapa Reddy,
been proposed to combat cancer (Ansari Moghaddam et al.,
2017). Green synthesized is also emphasized for copper NPs
2017; Mangalampalli et al., 2019; Kgosiemang et al., 2020).
in recent trends. Broccoli green extract was described as a
green and environmentally friendly precursor for copper NP
one-pot biosynthesis. The developed formulation was proven 4. In vivo application of metal nanoparticles
to be beneficial in the treatment of prostate cancer (Prasad
Several studies have been reported to check the anticancer
et al., 2016). The cytotoxicity of a chitin-based silver and cop-
effect of the metal NPs on tumor growth within animal mod-
per nanocomposite against human breast cancer (MCF-7)
els. Sriram et al. demonstrated the anticancer efficacy of bio-
cells was investigated. The inhibitory concentration (IC50) of
logically produced silver NPs in vivo using Dalton’s
the system was found to be 31 mg. Further findings revealed
lymphoma ascites. Silver NPs enhanced survival duration in
an increase in ROS production, decreased antioxidant
the tumor mouse model by almost 50% as compared to
enzyme activity, and membrane integrity degradation, con-
tumor controls. Additionally, silver NPs reduced the volume
firming the cellular cytotoxic effect of the copper–silver NPs-
of ascitic fluid in tumor-bearing animals by 65%, restoring
based nanocomposite (Solairaj et al., 2017).
normal body weight. The tumor volume was around 7.3 mL
in control mice but was considerably reduced to 2.6 mL in
3.2.4. Cerium Oxide nanoparticles the group treated for 15 days with silver NPs at a dosage of
Cerium oxide NPs surrounded by an oxygen lattice, have 500 nM (Sriram et al., 2010). In another study, selective radio-
shown potential in a variety of applications. These can sensitization of brain tumors using gold NPs was checked on
induce apoptosis in the cancer cells (Gao et al., 2014). mice. The successful treatment of brain cancers such as glio-
Through oxidative activation of the JNK apoptotic pathway, blastoma multiforme (GBM) is constrained in large part by
cerium oxide NPs make pancreatic cancer more sensitive to the cumulative dose of RT that may be safely administered
RT. Cerium oxide NPs cause cancer cells to produce more and by the blood–brain barrier (BBB), which prevents the sys-
ROS. The oxidation of thioredoxin 1 (TRX1), which results in temic anticancer medicines from reaching tumor tissue.
the activation of apoptosis signaling kinase 1, was demon- Hence, the developed NPs exhibited that mice treated with
strated to be triggered by ROS (ASK1). Enhanced JNK activa- gold NPs followed by RT had a longer median survival time
tion was thought to be the outcome of increased TRX1 (28 days on average) compared to mice treated with RT for
oxidation, based on the increase in ASK1 activation after co- only 14 days (p¼.011). In general, mice treated with dual
treatment with Cerium oxide NPs followed by RT modalities maintained a higher level of normal activity and
(Wason, 2018). lost less weight than untreated or single-modality mice. The
authors implied the successful extravasation of the gold NPs
into the brain as a result of tumor-induced rupture of the
3.2.5. Titanium nanoparticles BBB, where it radio-sensitized tumor cells to RT, resulting in
Natural forms of titanium dioxide include the inert minerals, enhanced tumor cell death and survival (Joh et al., 2013).
anatase, brookite, and rutile, all of which occur in varying Bis(2,4-pentanedionato)copper(II) encapsulated chitosan NPs
degrees of abundance. There are a lot of approaches to syn- were analyzed on mice model with control group having
thesize titanium dioxide NPs, including physical and chem- 1200 mm3 of tumor volume. The dose of 2000 lg/kg of body
ical. These methods of nanomaterial synthesis have some weight of both non-targeted and targeted NPs reduced
shortcomings, including cost, low biocompatibility, and sev- tumor volume to 600 mm3 and 125 mm3, respectively
eral secondary toxicities, as well as substantial environmental (Bhanumathi et al., 2018) (Table 3).
biosafety problems. As far as NP synthesis is concerned, bio-
genesis has been suggested. The biogenesis of titanium diox-
ide NPs uses a variety of organisms, including bacteria, algae,
5. Risk factors involved in the clinical application of
fungi, and plant materials. Biogenic titanium dioxide NPs
metal nanoparticles
have a unique size, shape, and biochemical functional corona Nanoparticles have been found and produced in large num-
that allows them to execute therapeutic effects at the bers, but conventional criteria for limiting exposure and
molecular level, such as anticancer, antibacterial, antioxidant, assessing their potential toxicity are lacking (Medici et al.,
larvicidal, and photocatalysis (Ikram et al., 2021). The use of 2021). Toxic effects are possible despite the particular advan-
titanium dioxide NPs in photothermal therapy for a melan- tages of nanomaterials due to their tiny size and high surface
oma cancer model was described by Muhammad et al. In area which have been shown to boost reactivity with bio-
the in vivo model, the average tumor size in the mice getting logical targets. Consumer and industrial products based on
titanium dioxide-PEG NPs with laser excitation treatment nanotechnology are nevertheless plagued by a slew of safety
674 J.-J. XU ET AL.

and sustainability issues (Grieger, 2019). Numerous problems

Zhen et al. (2013)

Zeng et al. (2020)

regarding the safety and long-term sustainability of con-

References
Yu et al. (2008)

et al. (2018)
sumer and industrial goods based on nanotechnology

Bhanumathi
remain unresolved (Najahi-Missaoui et al., 2021). Figure 8
depicts the various methods by which NPs might enter the
body. Inflammation, genotoxicity, and organelle failure in
cells are all directly linked to oxidative stress, which regulates
the toxicity of NPs. The activation of oxidative enzymatic

Tumor volume of 470 mm3

Tumor volume reduction
pathways results in the creation of nitrogen or oxygen-based
Effect of drug on
tumor growth

free radicals, which in turn causes oxidative stress. Protein,

to 53.72 ± 5.60% DNA, and lipid damage, as well as mitochondrial and endo-
38% reduction

plasmic reticulum dysfunction and eventually apoptosis or

ferroptosis, occur as a result of the relative imbalance or fail-
74.0%

ure of the intracellular free radical scavenging mechanism’s

defense capability under prolonged oxidative stress (Reuter
et al., 2010; Liao et al., 2020; Zhang et al., 2020).
5 mg/kg body
Dose of

The clinical application of the metal NPs can be achieved

weight
10 mg/kg
drug
5 mg/kg

1 mg/kg

only if the risks and toxicity are controlled, from production

to treatment. In a study, it was discussed that silver binds
strongly to sulfur (both organic and inorganic) in natural sys-
Control group

tems (fresh and sea waters) as well as wastewater. Due to

Doxorubicin

Doxorubicin
(drug)

the decreased solubility of silver sulfide, sulfidation of silver

Berberine
Cisplatin

NPs reduces their toxicity significantly, potentially limiting

their short-term environmental impact (Liao et al., 2020). The
manufacturing process of NPs is proposed by green synthesis
nanoparticle system

growth inhibition

utilizing plants, fungi, bacteria, and algae to avoid the high

on tumor growth

rate of harmful compounds and the severe environmental

Effect of

63% reduction

5 mg/kg body
89.6% tumor

conditions used in chemical and physical processes. When

weight
1 mg/kg

compared to physical and chemical methods of synthesis,

the green route of synthesis appeared to be safer and more
environmentally friendly (Levard et al., 2012; Kalpana &
Rajeswari, 2018). Copper NPs were synthesized by mixing
Tumor volume of 101 mm3

copper acetate solution with Eclipta prostrata leaf extract

Equivalent to 0.64 mg/kg

Tumor volume reduction

nanoparticle system

Equivalent to 10 mg/kg

without utilizing any surfactant or external energy. The anti-

to 31.18 ± 3.42%
Dose of the

oxidant and cytotoxic properties of copper NPs made from

doxorubicin

doxorubicin

Eclipta prostrata leaves extract were examined. E. prostrata

Table 3. Comparison of tumor growth with metal nanoparticles and clinical drugs.

leaf extract was reported as a good copper ion reducer, and

the biosynthesized copper NPs were less harmful to the
environment. The cytotoxicity of produced copper NPs
against HepG2 cells was demonstrated in in vitro anticancer
tests (Chung et al., 2017). The toxicity of NPs can also be
1287.27 ± 0.12 mm3)

reduced by using various polymers to coat metal NPs. To

tumor volume of
Mice (control group
Athymic nude mice
Animal model

K562-xenografted

transfer cisplatin prodrug (DSP) to the bone, PEG coated NPs

nude mice

formed of a Zn2þ coordination polymer were coupled with a

bone-seeking moiety, alendronate (ALN). In vivo biodistribu-
Mice

tion experiments revealed that DSP-Zn@PEG-ALN NPs intra-

venously delivered roughly fourfold more platinum to bone
metastatic lesions than to healthy bones (He et al., 2017).
Doxorubicin loaded superparamagnetic

RGD-modified apoferritin nanoparticles

Folic acid- and berberine-loaded silver

6. Conclusions and future perspective

iron oxide nanoparticles

Chemotherapy for cancer is still the most challenging area

Platinum nanoparticles

for academics looking for better clinical results. The use of

Type of nanoparticle

targeted drug delivery for the treatment of cancer has the

nanomaterial

potential to improve efficacy while lowering the adverse and

side effects. Nanotechnology has revolutionized medical
research. The metal NPs are among the candidates for next-
generation anticancer treatment. Metal NPs have been
 DRUG DELIVERY 675

Figure 8. Exposure routes, ways of uptake, translocation, and distribution of NPs into the human body (Medici et al., 2021).

extensively studied due to their remarkable flexible physical for clinical use of metal NPs in cancer treatment and drug
and chemical properties. The current research has led to delivery, as well as new approaches to evaluate the efficiency
achieving various advantages with metal NPs including low and safety measures of such NPs. On top of that, research
cost, ease of synthesis, and the flexibility to control the form scientists are struggling to come up with optimum amounts
and size of the NPs. Green synthesis has also eliminated the of phytochemical conjugated metal NPs for cancer patients
risk of harsh and environmentally unfriendly compounds and and the most effective means of administering these doses.
solvents. Furthermore, due to their unique plasmonic proper- Metal NPs, on the other hand, will undoubtedly become a
ties, noble metal NPs provide a reliable means of tracking major clinical tool in the fight against cancer once these con-
nano-complex therapeutic carriers within the body, allowing cerns are resolved.
for a more efficient therapy with a lower chance of side
effects than traditional therapies. These NPs would allow
Disclosure statement
practitioners to diagnose and track the progress of treatment
during treatment. Additionally, non-noble metal NPs are No potential conflict of interest was reported by the author(s).
cost-effective and possess specific properties like hyperther-
mia and magnetic properties.
Funding
Several studies have demonstrated the efficacy of metal
NPs as a future of cancer treatment, and many metal NP This work was supported by the National Natural Science Foundation of
compositions are currently in preclinical and clinical trials. China (No. 81802674 to JJX), Natural Science Foundation of Zhejiang
Province (No. LY21H160049 to JJX), and Medical Health Science and
But a lot of concerns need to be addressed yet. The tumor
Technology Project of Zhejiang Provincial Health Commission (No.
imaging will be done with metal NPs to determine its exact 2021KY482, No. 2020KY008 to JJX).
stage, and tumor therapeutic methods will be developed in
which the toxicity levels (prevalent in existing approaches)
are completely eradicated. However, various criteria related ORCID
to their manufacturing and use must be examined before Xiao-Yi Chen http://orcid.org/0000-0001-9160-7016
they can be used in clinical trials. These precautions include
control of techniques of preparation, repeatability, stability,
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