Recent Advancements of Anti-cancer Nanomedicine in Breast Cancer

Jiachen Li

Indiana University Bloomington, U.S.A.

Keywords: Nanomedicine, Cancer, Anti-Cancer, Cancer Treatment.

Abstract: Nanomedicine is a novel type of cancer treatment that has been applied to clinical practice for its identified

safety and potency against cancer cells and safety. Conventional cancer treatments such as surgery,

radiation, and chemotherapy work generally well but inevitably bring severe adverse reactions and

sometimes unsatisfying results. Breast cancer is one of the most major cancer with high incidence rate and

mortality rate, characterized by high risks and a great reduction in of life quality of life with high incidence

rate and mortality rate. In the past three decades, nanotechnology emerged to giving rise to novel forms

offer anti-cancer drug delivery systems and offering greater therapeutic therapeutical advantages than

traditional cancer treatments can do. With the incorporation of nanocarriers, higher drug loading efficiency,

targeted delivery, enhanced bioavailability, and stronger cytotoxicity, and less side effects can be achieved.

This paper shows the recent developments of nanocarrier-incorporated anti-cancer drugs with specific to

breast cancer. Ways of newly synthesized drug loaded nanoparticles alleviating side effects from

conventional treatments and improving therapeutic effects are stressed in this paper.

1 INTRODUCTION

Cancer, the second leading cause of death, is a group

of diseases induced by uncontrollable abnormal cell

division and replication. According to the World

Health Organization’s International Agency for

Research on Cancer Global Cancer Observatory

(GLOBCAN), in 2018, there were 18 million new

cancer incidences and 9.5 million related deaths

worldwide, and by 2040 the number of new cases

will rise to 29.5 million and the number of related

deaths would be 16.4 million (Hulvat, 2020).

Conventional treatments for cancer are surgery,

radiation, and chemotherapy. For cancers in early

stage, surgery and radiation work well. Surgery is an

important approach to tumors for the ability to

remove the lower grade benign tumors. Surgery,

however, becomes extremely difficult when the

tumor is located on unreachable sites. Moreover,

side effects like headaches, fatigue, and further

damage to the brain tissue may happen after the

surgery. Radiation is a cancer therapy applying high

energy radiation to eliminate cancer cells, which is

not an ideal approach because there is an annual and

a lifetime exposure limit, and it inevitably affects

adjacent normal cells. Radiation may also bring

https://orcid.org/0000-0001-5389-6128

adverse symptoms such as nausea, hair loss, and

diarrhea. The other side effect is that when

metastasis occurs, the surgery and radiation become

ineffective. Metastasis refers to that the secondary

cancer develops and spreads to different sites in the

body far from its initial site. When the tumor is

metastasized, surgical removal may enhance tumor

recurrence (Tohme, Simmons, Tsung, 2017).

Similarly, radiation promotes metastasis and

increases the possibility of recurrence, suggesting by

abundant clinical data (Vilalta, Rafat, Graves, 2016).

Later, since 1940s, chemotherapy has been

utilized as a treatment of cancers. Chemotherapy is

characterized by fast killing of cancer cells by

delivering chemical agents that disturb cancer cell’s

replication. It is used to treat metastatic cancer,

which has spread to other parts of the body. The

drugs are delivered through the bloodstream and

reach cancer cells; however, chemotherapy has some

severe problems. Chemotherapy eliminates normal

cells along with cancer cells. Moreover, nausea,

vomiting, and neutropenia are commonly observed

after receiving chemotherapy.

Breast cancer is one of the major cancers with

high incidence and mortality rate (DeSantis, Ma,

Gaudet, et al 2019). Female breast cancer has

become the leading cause of global cancer incidence

152

Li, J.

Recent Advancements of Anti-cancer Nanomedicine in Breast Cancer.

DOI: 10.5220/0011192400003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 152-159

ISBN: 978-989-758-595-1

in 2020, in which unhealthy lifestyle plays a role in

it other than hormonal factors. The risk of breast

cancer is associated with personal lifestyle. Obesity,

insufficient physical activity, and high alcohol

consumption are risk factors of breast cancer which

are many people are currently having.

The specific cause of cancer is still under

investigation. Up until now, scientists believe that

the formation of cancer is associated with oncogenes

and tumor suppressor genes. Oncogenes are found to

be expressed at a high level in cancer cells. They

emerge when proto-oncogenes, which promotes

positive cell growth, mutate to become activated

oncogenes (Lam, Schmidt, 2012). As a result, the

cell starts to uncontrollably divide and promotes

carcinogenesis (Lam, Schmidt, 2012). On the

contrary, tumor suppressor genes, also called anti-

oncogenes, regulate normal cell division and inhibit

cell proliferation (Krasin, Davidoff, 2012). The

inactivation of tumor suppressor genes leads to their

malfunction, inducing infinite cell replication, or the

development of malignancy. (Lam, Schmidt, 2012).

Most current anti-cancer drugs or therapies either

kill fast-growing cancer cells along with normal

cells (e.g., chemotherapy, radiation) or target

specific proteins inside or outside cancer cells. (e.g.,

small molecule drugs and monoclonal antibodies).

Target therapies can be identified through the

examination of highly expressed proteins in cancer

cells; while in normal cells, the amount of the same

kind of proteins remains low (Kampen, 2011). For

example, human epidermal growth factor receptor 2

(HER2) is a protein overexpressing on the surface of

approximately 20-30 % of breast cancer cells. (Mitri,

Constantine, O’Regan, 2012). Trastuzumab and

Pertuzumab are antibodies that target HER2. (Kunte,

Abraham, Montero, 2020). Another difference

between cancer cells and normal ones that inspire

novel drugs is that cancer cells require large supply

of oxygen to sustain cell replication and to spread.

Cancer cells often experience hypoxia, the decreased

level of oxygen (McKeown, 2014), so the average

oxygen level is lower in cancer cells. Angiogenesis,

the formation of new blood vessels, is observed a

large increase when benign tumor transforms into

malignant one (Brustmann, Riss, Naudé, 1997),

which is the induced response of hypoxia (Chen,

Endler, Shibasaki, 2009). Under such circumstances,

angiogenesis inhibitors are applied to restrain the

cancer blood vessel growth (Klagsburn, Moses,

1999). Clinically approved drugs are Trastuzumab

and Pertuzumab for advanced breast cancer, only to

name a few. Along with conventional treatments,

anti-tumor target drugs alone such as Trastuzumab

and Pertuzumab could bring serious side effects

(Bines, Clark, Barton, et al, 2021) Given such

situation, a less painful approach with higher

therapeutic efficiency is needed.

In recent years, people have gained greater

understanding of nanomedicine as a novel approach

to cancer treatment. Nanomedicine is the application

of nanotechnology for medical therapeutics by using

nano-scaled agents to treat diseases. Nanomedicine

possesses properties of targeted delivery, small-scale

size, decent permeability, and bioavailability (Patra,

Das, Fraceto, et al, 2018). Nanodrugs synthesized by

materials such as liposomes, polymers, inorganic

particles, and peptides are proved to be feasible

ways to enhance the effectiveness of cancer

treatments by the clinical data. They target specific

to prevent the damage to normal tissues and cells,

thereby exhibiting high cytotoxic concentration in

tumors. The encapsulation of drugs into nanocarriers

protects anti-cancer drugs from degradation,

improving the drug delivery efficiency (Patra, Das,

Fraceto, et al, 2018).

Previous researches have done to integrate the

advantages and clinical practices of nanocarriers

with a broad focus on several cancers. However,

within the rapid development of nanomedicine in

past ten years, new forms of nanodrugs and clinical

applications emerge; therefore, an update that

includes the analysis of past nanomedicine and how

they evolve within times with more specific focus is

needed.

This paper provides a description of recent

nanomedicine-incorporated cancer treatments with

specific to breast cancer. The specific advantages

and working mechanisms of common nanoparticles:

liposome, porous silicon, and dendrimer are

described. Disadvantages of traditional drugs such as

Tamoxifen, Doxorubicin, and Trastuzumab, and

how newly synthesized drug loaded nanoparticles

address these problems and offers therapeutic effects

are stressed in this paper.

2 COMMON NANOMEDICINE

FOR BREAST CANCER

TREATMENT

Nanomedicines has been applied to clinical practice

and they are still under intensive investigation, for

its potential and effectiveness of anti-tumor.

Liposome, porous silicon, and dendrimer are

commonly used nanocarriers to treat breast cancer.

Their working mechanisms and advantages are

Recent Advancements of Anti-cancer Nanomedicine in Breast Cancer

153

briefly described below, for which are core concepts

in understanding later introduction of nanoparticle-

incorporated drugs.

Figure 1: Scheme diagram for six nanocarriers: (a)

Liposome, (b) Porous Silicon, (c) Dendrimer.

2.1 Liposome

Liposome is a spherical nanosized vesicle that

consists of an aqueous core and phospholipid

bilayers. The bilayer is composed of hydrophilic

heads and hydrophobic tails, making it amphipathic.

As a result, liposomes can carry both hydrophilic

and hydrophobic drugs without degeneration.

Normally, drug-loaded liposome works in four

patterns: (Sharif, Fazle, Nazir, 2006)

1. Endocytosis by phagocytic cells, absorbing

substances by cell membrane’s engulfment

(Phagocytosis and Intracellular Killing,

2012). Adsorption to the surface of the cell

by interactions with components on the

surface.

2. Fusion with the plasma membrane by the

interaction between phospholipid bilayers

and plasma membrane, releasing the

contents loaded in the core of liposome.

3. Transfer of liposomal membranes to

cellular membranes.

2.2 Porous Silicon (pSi)

Porous silicon is a sponge-like nanostructure in

which microstate crystalline silicon is introduced.

The pSi has proved to possess excellent

biocompatibility and biodegradability due to its

unique porous structure and chemical properties

(Kumeria, McLinnes, Maher, Santos, 2017). Porous

silicon is identified by large surface area and internal

volume, allowing high loading capacity and

enhanced adsorption ability (Santos, Mäkilä,

Airaksinen, Bimbo, Hirvonen, 2014). Once pSi

arrives at the targeted site and releases the loaded

drug, it degrades into silicic acid which is harmless

to human body and easily removed by kidneys

(Manj, Chen, Rehman, Zhu, Luo, Yang, 2018).

2.3 Dendrimer

Dendrimers are ordered, branched three dimensional

polymetric molecules. They have symmetric and

monodisperse structure which consists of a core,

branched, symmetric dendrons, and terminal

functional groups (Abbasi, Aval, Akbarzadeh, et al,

2014) The internal cavities of dendrimers enable the

encapsulation of drugs, making excellent stability

and solubility (Santos, Veiga, Figueiras, 2020).

Dendrimers’ properties can be possibly modified

and controlled, for various terminal groups attached

are responsible for the interaction of dendrimers and

external molecules (Han YL, Kim SY, Kim T, Kim

KH, Park JW, 2020).

3 BREAST CANCER

3.1 Tamoxifen

Tamoxifen (TMX), an antiestrogen, is a traditional

clinically proved hormonal treatment for breast

cancer (Yang, Nowsheen, Aziz, Georgakilas, 2013).

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154

It has dual mechanism of action: (1) inhibiting

estrogen action and blocking the binding of estradiol

), (2) binding with DNA after metabolic

activation and initiating carcinogenesis (Yu, Bender,

2001, Craig Jordan, 1992). TMX is reported to

reduce the incidence of oestrogen positive breast

cancer by 38% among high-risk patients (Singh,

2021). It decreases the taker’s death rate and

recurrence rate (Gray, Rea, Handley, et al, 2013).

TMX, however, induces side effects (Osborne,

1998). Besides those common adverse reactions

such as hot flashes, sleep problems, and vaginal

dryness, it stays on estrogen receptors in tumor

tissue for several months after the treatment is

stopped and gives false negative results (Osborne,

1998). Moreover, TMX treatment promotes the

development of endometrial cancer and increases the

risk of it (Bergman, Beelen, Gallee, Hollema,

Benraadt, Van Leeuwen, 2000).

Porous silicon (pSi) based nanomaterials have

been identified the potential to be excellent carriers

for cancer treatment. Inspired by the side effects of

TMX and the advantages of pSi, researchers

synthesized TMX-loaded pSi nanoparticle to further

improve the bioavailability of TMX (Haidary,

Mohammed, Córcoles, Ali, Ahmed, 2016). The drug

release is controlled by the rate of degradation of pSi

due to its biodegradable property (Haidary,

Mohammed, Córcoles, Ali, Ahmed, 2016).

Biocompatible, non-toxic material chitosan and

silica xerogel hybrid is used on surface coating to

prevent infection, and the hybrid coating produces

outstanding drug release results (Haidary,

Mohammed, Córcoles, Ali, Ahmed, 2016).

The price of chemicals needed for preparation,

hydrosilylation, and bioactive coating is moderate.

For instance, 2.5 L 37% hydrochloric acid is about

$112 on Sigma Aldrich, while only 0.5 mL diluted

HCI (2%) is needed for silica xerogel preparation,

similar situation to other chemicals required.

Obstacles of industrial production of TMX-loaded

pSi nanoparticle, however, still remain. The process

of preparation of pSi particle, the hydrosilylation,

and the bioactive coating, is complicated, making

the large production expensive and time-consuming.

3.2 Doxorubicin

Doxorubicin (DOX), an antibiotic derived from

bacterium Streptomyces peucetius, is another

commonly used anti-breast cancer agent with strong

effectiveness (Christowitz, Davis, Isaacs, Van

Niekerk, Hattingh, Engelbrecht, 2019). The primary

working mechanism of DOX involves intercalation

of DNA pairs, breaking the DNA strand and

inhibiting the DNA and RNA synthesis (Agrawal,

2007). DOX brings severe adverse effects like other

widely applied agents. For instance, DOX is highly

toxic and it increases the risk of potentially fatal

cardiotoxicity; therefore, its dose should be limited

strictly (Zhao, Ding, Shen, Zhang, Xu, 2017). Other

deleterious side effects include myocardial damage

and heart failure (Redfors, Shao, Råmunddal, et al,

2012).

When treating tumors, DOX alone is of rather

low drug loading efficiency due to the hamper of

abnormal, tortuous blood vessels; only 5-10% of

drugs enter the tumor tissue and take effect (Chang,

Li, Lu, Jane, Wu, 2013). To increase the higher drug

load efficiency and to achieve better therapeutic

effects, PEGylated liposomal doxorubicin (PLD), a

formulation of doxorubicin packed into liposome

with polyethylene glycol outer coating, was created

by reseachers (Green, Rose, 2006). With

nanocarrier’s encapsulation, 15,000 DOX molecules

per vesicle with over 95% drug loading efficiency is

achieved (Chang, Li, Lu, Jane, Wu, 2013, Gabizon,

2001). Small size of liposomal carrier contributes to

better tumor accumulation; the smaller the size, the

better tumor accumulation (Gabizon, 2001).

Moreover, PLD is observed to have longer half-life

and slower clearance than non-PEGylated liposome

and free DOX, which means that PLD has the ability

to achieve longer circulation time (Gabizon, 2001).

All in all, PLD has revealed great potential in

making a perfect anti-cancer practice.

The therapeutic value of DOX is further

improved by the encapsulation of nanocarriers on

which modified by other tumor target chemical

agents. For example, after the Clot-binding

pentapeptide Cys-Arg-Glu-Lys-Ala (CREKA) has

gained the recognition of the ability to recognize

fibrin-fibronectin complexes that overexpress in

tumor vessel endothelium and stroma rather than

normal cells, making CREKA a target peptide of

effectiveness and precise target delivery (Shi,

Zhang, Liu, et al, 2018, Jiang, Song, Yang, et al,

2018). In a recent study, CREKA modified

liposomal DOX (CREKA-Lipo-DOX) has been

synthesized and proved its therapeutic effects (Jiang,

Song, Yang, et al, 2018). Compared to free DOX

with rapid release, the drug release of CREKA-Lipo-

DOX is more sustained with little burst; the release

of CREKA-Lipo-DOX is slightly faster than those of

PLD.[40] Though PLD improves the anticancer

efficiency of free DOX, CREKA-Lipo-DOX can

significantly inhibit cancer cell growth and

metastasis in vivo. Furthermore, CREKA-Lipo-DOX

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is safer than PLD and DOX (Attia, Anton, Wallyn,

Omran, Vandamme, 2019). Study demonstrates that

CREKA-Lipo-DOX shows no severe cardiotoxicity

and all other organs are of normality without

obvious histopathological lesions (Jiang, Song,

Yang, et al, 2018).

The needed chemicals and materials in this study

are of large amount and overall price of all material

is high. The researchers implemented the thin-film

hydration method to prepare liposomes for its

simplicity; however, this method may result in no

controlled size in production of liposomes and poor

encapsulation efficiency of hydrophilic drugs

(Nkanga, Bapolisi, Okafor, Krause, 2019). Also, this

study mainly focuses on anti-metastasis efficacy;

more data specifically about anti-tumor is needed for

further development.

3.3 Trastuzumab

Trastuzumab is a traditional anti-breast cancer

monoclonal antibody targeting HER2 (a gene that

activates the growth factor signal) positive cells

(Bines, Clark, Barton, et al, 2021). Trastuzumab

binds to the juxtamembrane portion of the domain of

HER2 receptor and prevents the overexpression of

HER2 (Hudis, 2007). In general, patients who

receive Trastuzumab improves all clinical outcome

parameters including overall survival rate of

patients.

Despite these benefits, Trastuzumab

induces serious cardiac and gastrointestinal side

effects after investigating the toxicity associated

with it (Huszno, Leś, Sarzyczny-Słota, Nowara,

2013). In addition, diarrhea, fever, nausea is

commonly observed after treatment.

A new form of Trastuzumab treatment has been

invented to improve its therapeutic efficiency. By

covalently attaching fluorinated dendrimer to

Trastuzumab, Trastuzumab-dendrimer-fluorine drug

delivery system targeting the HER2 receptor on

breast cancer cells is synthesized by researchers

(Bartusil-Aebisher, Chrzanowski, Bober, 2021). The

incorporation of

F increases the lipophilicity and

hydrophobicity of drug delivery system, while the

use of PAMAM-G5 dendrimer enhances the cellular

uptake of the drug delivery system and increases

biocompatibility (Bartusil-Aebisher, Chrzanowski,

Bober, 2021). In addition, Trastuzumab-dendrimer

drug delivery systems have shown enhanced

solubility and controlled release of Trastuzumab in

comparison to the pure drug alone (Bartusil-

Aebisher, Chrzanowski, Bober, 2021).

The Trastuzumab-dendrimer drug delivery

research was done in vitro, which means that further

study must be done to prove its safety and feasibility

before clinical use, but with long and complicated

synthesis to obtain the final product, the in vivo

stage test might face more challenges.

4 CLINICAL APPROVALS OF

NANOMEDICINE

Nanomedicine has been the frontier technology in

medicine. Since 1990s, large amounts of designed

nanoparticles were created and entered clinical trial.

However, few of them were able to be approved for

clinical use. Nanoparticles being declined exhibit

extra strong cytotoxicity, unwanted adverse effects,

and low efficiency of targeted delivery (Seok, Bae,

2018).

Figure 2: FDA approved nanomedicine since1990s

(Anselmo, Mitragoti, 2019).

Since the approval of Doxil® in 1995, more

newly made nanomedicine emerge in 2000s with

significant breakthrough of drug delivery efficiency

gained approval (Seok, Bae, 2018). Although the

number of approved nanomedicines is not satisfying

compared to the fact that numerous novel

nanoparticles are ongoing for clinical trial, scientists

continue to make progresses towards improving

synthesis strategies.

5 CONCLUSIONS

The presence of nanoparticles provides an

alternative way to more effective cancer treatments

other than conventional therapies. This paper

includes the working mechanisms and advantages of

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

156

partial common nanoparticles, including pSi,

liposome, polymeric materials, and peptide drugs.

They possess the characterization of small size,

high drug loading capacity and efficiency, enhanced

bioavailability, and harmlessness to human body,

making them ideal approaches to anti-cancer

practice. Nanotechnology is still evolving rapidly;

current existing nanoparticle-based drug delivery

systems will be refined, and newly designed ones

will emerge in the future. Although huge amounts of

nanocarrier incorporated drug delivery system with

excellent therapeutical effects and clinical values

have been successfully synthesized in laboratory and

entered the clinical trial, clinically approved ones are

relatively fewer. While the majority of them are

passive targeting nanoparticles, there are no active

targeting ones approved from 2007 to 2017 (Narum,

Le T, Le DP, et al, 2019). From future perspective,

active targeting nanoparticles need to be further

investigated, for they can be applied to the situation

where therapeutic drugs have difficulties crossing

the cell membrane (Attia, Anton, Wallyn, Omran,

Vandamme, 2019). Throughout the paper, we know

that the choice of nanoparticle depends on specific

cancer type, the cost of production, prior studies on

possible adverse reactions and research parameters,

and studied nanodrug-induced response in vivo, to

ensure the nanodrug’s safety and effectiveness

(Attia, Anton, Wallyn, Omran, Vandamme, 2019).

Given that, much efforts should be devoted to

investigate safe and feasible nanoparticle-based drug

delivery system for cancer treatments.

The synthesis procedures of previously described

nanomedicine are generally at high cost: expensive

chemicals, bioreactors, equipment, and instruments

are required, and more animal and clinical testing

will need to be completed before clinical

approvement. The use of organic solvents and

complicated steps to synthesize nanoparticles cannot

ensure the purity of the product. Future

investigations can focus on the alternative ways of

creating nanoparticles with fewer steps and lower

price when the yield, purity and stability can be

sustained.

All in all, this paper stresses recent advance anti-

cancer nanomedicine within a short time frame with

specific focus on breast cancer treatments. This

paper possesses potential time limitations due to the

fact that nanomedicine continues to advance. Future

investigation can cover lower cost nanomedicine

production methods, new clinical practices of

nanodrugs on different types of cancer and

treatments, and safer, more therapeutically effective

synthesis design for the time being.

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