Nanotechnology and its Role in Cancer

Treatment

By: Vanessa Isla and Japun Padda

Humber College

REGA 505 – Biotechnology

Peivand Pirouzi

December 6, 2012

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Introduction

The World Health Organization (WHO) claims that cancer is the leading cause of death

worldwide accounting for about 7.9 million deaths in 2007, and deaths are estimated to rise to

about 12 million by the year 2030 (WHO 2011). The rates for new cancer cases and deaths in

the U.S. for the year 2007, reported by the Center for Disease Control and Prevention, were

543.2 new cases/100, 000 and 217.8 deaths/100, 000 for men, and 409.4 new cases/100, 000 and

150.9 deaths/100, 000 women (CDC 2011). In Canada, the incidence rate for all cancers in the

year 2007 was reported to be 405.2 per 100, 000 for men and women (PHAC 2011). It is evident

that cancer is a worldwide concern, and will continue to be a major public health concern

especially since the incidence rates are considerably. Cancer has always been a focus of research

where there is always a quest for new ways to detect and treat cancer, but the improvement and

development of treatment strategies seemed to remain constant over the past 30 years with no

major innovations (Farrell et al. 2011).

The application of nanotechnology to medicine may be the solution to finding innovative ways to

treat cancer more effectively at the molecular level. Nanotechnology is defined as “intentional

design, characterization, production, and applications of materials, structures, devices, and

systems by controlling their size and shape in the nanoscale range (1 to 100 nm).” (Gonsalves et

al. 2008; Kim et al. 2010). The medical application of nanotechnology led to the emergence of a

new field known as “nanomedicine”, which can serve as a way to improve medical diagnosis,

treatment, and prevention of diseases using molecular tools and knowledge of the human body

(Gonsalves et al. 2008). Nanomedicine does not only entail the therapeutic products themselves

but also the promise of combining its ability to be able to deliver the therapeutic component

successfully to its target cell(s) and release it as a response to a physiological event thereby

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performing a specific task (Chan 2006). The promising attributes of applying nanotechnology to

cancer therapy through nanomedicine holds great potential for improving the health of the public

while possibly finding innovative ways to effectively treat cancer.

What makes Nanomedicine attractive for cancer therapy?

In hopes of fostering further new ways to approach cancer research and care, in 2004, the

National Cancer Institute’s (NCI) Alliance for Nanotechnology in Cancer was initiated for the

purpose of: (1) providing researchers with the opportunity to study and manipulate

macromolecules during the earlier stages of cancer, (2) detecting cancer-related molecules in a

sensitive and rapid manner, (3) providing support for novel and highly effective therapeutic

agents (Farrell et al. 2011; Amiji 2010).

The uses of nanotechnology applications for cancer therapeutics are focused on improving drug

delivery and toxicities associated with cytotoxic chemotherapies (Amiji 2010). The multi-

functionality of nanoparticles is what makes them quite ideal in treating cancers. Nanoparticles

have the ability to deliver the therapeutic component directly to the tumour site while selectively

eradicating cancerous cells without forfeiting healthy cells in the process (Farell et al. 2011).

This allows for fewer side effects that are commonly associated with chemotherapies for cancer.

Currently, the primary treatment options for cancers are: surgical procedures to remove

tumour(s), radiation, and chemotherapy (Goncalves et al. 2008). It is important to bear in mind

that not all cancers will possess the same characteristics; therefore not all chemotherapeutics will

have desirable effects, or selectivity, towards all types of cancer (Li et al. 2011). This non-

specificity that some therapeutics may have can result in poor therapeutic efficacy and also

damage to normal tissue, such as bone marrow, skin, kidney, and gastrointestinal mucosa (Nalwa

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and Webster 2007). Nanomedicines are believed to be multifunctional, which could resolve the

issue that other therapeutics have with biological barriers. In regards to nanotechnology, Pope-

Harman et al. (2007) suggests that “selective targeted therapy will be enhanced through the use

of multimodal targeting, in which therapeutics are localized physically by more than one

mechanism”. Potential solutions that nanomedicine may have to surpass biological barriers are to

provide therapeutic agent(s) that have the ability to comprise of co-localized delivery. Also, an

alternative means of administration besides the use of injection, which can be uncomfortable for

some patients. Instead, such materials can be inhaled or swallowed (Pope-Harman et al. 2007).

Longer dosing intervals can also be made possible using nanomaterials, and it could potentially

increase the amount of drug that reaches malignant cells, therefore potentially minimizing

adverse effects (Pope-Harman et al. 2007).

All of these potential factors that are contributed by using nanomedicine can play a major role in

improving patient compliance, which could overall improve the efficacy of the therapeutic agent

in use. What should be considered when developing an effective nanoparticle drug delivery

system is drug targeting, which may guarantee preferential detection and killing of cancer cells

while minimizing the effects on healthy cells (Nalwa and Webster 2007; Loomis et al 2011).

Nanoparticles’ have unique physical properties (size, charge, biocompatibility, solubility) which

can be manipulated to increase circulation half-life. In turn, this can lead to increased

accumulation of particles and associated drug cargo at the tumor site (Farrell et al. 2011). Figure

1 illustrates a multifunctional nanocarrier which is an ideal design for a nanoparticle for use as a

drug delivery shuttle for a cancer therapeutic (See Appendix A). Ways in which the

multifunctionality of the nanoparticle can be engineered so that it may serve as a mediate drug

delivery system could be to (1) incorporate a coating of a neutral polymer, such as poly(ethylene

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glycol), which would allow for evasion of the mononuclear phagocyte system resulting in

prolonged circulation in the bloodstream. This would also help stabilize the particle as well as

decrease its likelihood of being cleared from the plasma (Loomis et al. 2011). (2) Incorporation

of imaging agents into the core of the nanoparticle can also be done, which would allow for “real

time visualization” of the nanoparticle’s biodistribution. These agents could play a role in cancer

diagnosis and prediction of therapy (Loomis et al. 2011). (3) Incorporation of a capsule

containing a payload of the therapeutics in use can be done, in which the nanoparticle will

release upon interaction with the selected cell (Loomis et al. 2011). (4) Targeting ligands can

also be incorporated onto the surface of the nanoparticle which would allow for receptor

mediated endocytosis into the selected cell, thereby increasing delivery specificity (Loomis et al.

2011). (5) A fusogenic lipid can also be incorporated to trigger release of the nanoparticle’s

contents, for example it can do this once placed in an acidic environment (Loomis et al. 2011).

Trigger release is significant in the success and functionality of the nanoparticle if it were to

serve as a drug carrier. The reason for this is solely due to the requirement of its contents to be

released in order for the drug to be available and cause an effect. The ways in which the drug

release is timed as well as the degree of its release are important for tumour therapy (Loomis et

al. 2011). Strategies that convey the ability to control the trigger to release the contents of the

nanoparticle are essential in developing an effective therapeutic drug delivery system (Loomis et

al. 2011). Examples of triggers are heat, pH change, ultrasound, and enzymes, which all may

control the release of the nanoparticle’s contents.

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Technical Aspects of the use of Nanomedicine for Cancer Treatment

In order for nanoparticles to be used for biomedical applications it needs to be biocompatible and

biodegradable so that the nanoparticles can be excreted by the kidneys or bile, and does not have

toxic effects on the individual (Lamprecht 2009). Nanoparticles are ideal because they are able to

cross biological membranes and access cells, tissues, and organs that larger particles cannot, such

as molecules of various drugs (Pathak et al. 2007).

Drug payloads can be quite large, due to large surface-to-volume ratios at the nanoscale (Farrell

et al. 2011). Engineers are able to choose a variety of ways to “dress” the surface of a

nanoparticle that could make it more biocompatible and selective in its targeting of biological

molecules (Kim et al. 2010). This can be done by coating it with polymers or biorecognition

molecules as described in figure 1. With nanomaterials, the high ratio of surface area to volume

permits high surface loading of therapeutic agents (Kim et al. 2010). The next question to be

asked is how all these characteristics of a nanomedicine work together in treating cancer:

Tumours normally lack blood vessels of their own and therefore steal their nutrients (i.e. oxygen

and glucose) from the surrounding tissues during the earliest stages of cancer (Grossman and

McNeil 2012). More of the nutrients are directed towards the cells at the tumours periphery than

its core, therefore starving the core (Grossman and McNeil 2012). These starving cells of the

tumour’s core releases proteins, which signal the tumour’s “oxygen-starved state”, that diffuse

outward until reaching nearby blood vessels. Growth of new blood vessels are stimulated and

can then supply the tumour with oxygen and other nutrients thereby sustaining rapid cell growth

and replication. This whole process is known as “angiogenesis” and is the hallmark of cancer

(Hanahan and Weinberg 2000). The rapid growth of these angiogenic cells cause these cells to be

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irregular and leaky resulting in more and larger gaps in their walls compared to healthy blood

vessels (Grossman and McNeil 2012). Depending on where the tumour is located in the body

and what stage of development it is in the size of the gaps vary but range from a few hundred

nanometers to a few microns (Grossman and McNeil 2012). Nanoparticles that are between

10nm to 300nm in diameter can significantly pass through these gaps in the blood vessels

supplying tumours but not significantly penetrate healthy tissue (where the pores in normal blood

vessels are 2-6nm in size) (Grossman and McNeil 2012).

Nanoparticles are also able to selectively accumulate in tumour tissue by means of a

phenomenon called the “enhanced permeability and retention” (EPR) effect (Grossman and

McNeil 2012). The drug payload is then released by an associated trigger and eventually the

cancer cells of the tumor undergo apoptosis.

Approved FDA Nano-drugs

There are already FDA-approved nano-drugs on the market: Abraxane® and Doxil® (illustrated

in Figure 2, See Appendix B.) both have proven to be beneficial to cancer patients (Farell et al.

2011, Grossman and McNeil 2012). Abraxane® is a nanoparticle of the drug paclitaxel, which is

a chemotherapeutic that is poorly soluble in water. Abraxane® uses a nanoparticle that is bound

by the blood protein albumin to encapsulate and solubilize paclitaxel. Abraxane® has proven to

be more effective and less toxic than is comparator Taxol® (Grossman and McNeil 2012).

Doxil® is a nanosized liposome composed of crystals of the drug doxorubicin encapsulated in a

lipid layer and coated with polyethylene glycol (PEG). Free doxorubicin is commonly known to

be toxic to the heart and cause damage to the heart’s cardiac muscles. The nanoparticle delivery

system of Doxil® allows for the distribution of the drug in the body with minimal distribution to

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the heart. Doxil® is known to cause ulcerations to the skin due to the distribution of the drug to

the skin but this adverse side effect may be more preferable than cardiac toxicity (Grossman and

McNeil 2012). Based on testings done to compare the side-by-side efficacy of the nanodrug to

the free drug, nanodrugs were more efficacious and allowed for the use of a lower dosage

(Farrell et al. 2011). Today there are about 82 ongoing clinical trials involving nanoparticles to

treat cancer (refer to Table 1 in the Appendix for examples of nanomaterials in clinical use for

cancer therapy) (Grossman and McNeil 2012).

Existing Concerns About the use of Nanomedicine

Existing concerns about nanomedicine and its use for cancer therapy involve the confusion and

disagreement with the current definition of “Nanotechnology”. It is considered an umbrella term

used to define products, processes and properties at the nano scale. In terms of safety and

regulations of nanotechnologies in the use of cancer treatment, issues of biodistribution and

toxicity must be addressed. Biodistribution and cellular uptake of nanoparticles depends on its

size, shape and other properties (Farrell et al. 2011). There is also the concern of mass producing

nanomedicines. The ability to reproducibly manufacture nanomedicines at large scales with high

levels of control over the physicochemical properties remains a major hurdle (Grossman and

McNeil 2012). Though many labs can make nanomedicines at the milligram levels for proof-of-

concept in vitro studies, the costs and manufacturing challenges associated with making large-

scale batches of the same quality remain great (Grossman and McNeil 2012). With this in mind,

nanomedicines are indeed expensive. Using the two FDA-approved nanomedicines in the

market for cancer therapy as an example, average per-dose cost of Abraxane and Doxil exceed

$5000 in 2009 compared with less than $500 for Taxol and less than $200 for doxorubicin

(Grossman and McNeil 2012). However, nanomedicines are documented to be less toxic to

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healthy tissues and provide a significantly better quality of life than the molecular counterparts

but with only modest improvements in overall survival (Grossman and McNeil 2012). With this

in mind, since nanomedicines are considerably more expensive than their small-molecule

competitors, they must show a dramatic increase in patient survival in their clinical data

(Grossman and McNeil 2012).

Improvement in Nanotechnology – FDA Regulations

Currently, FDA’s regulatory regime is based on the main idea that large particle versions of

products are considered to be safe, and this can be presumed that nanoversions of the same bulk

products would be safe as well. FDA believes that both bulk products and nanoparticles are

“bioequivalent”. This regulatory regime is scientifically flawed. Firstly, not all nanoscale

materials are created equal and their toxicities depend on factors such as size, charge, shape,

polarity, etc” (Bawa, 2011). In addition, “as the size of particle decreases, a great proportion of

its atoms are located on the surface relative to its core, often rendering the particle more reactive

over its conventional bulk counterpart” (Bawa, 2011). The decrease in particle size increases

reactivity of the particle, dissolution rate, saturation solubility, and in whole, its toxicological

risk and a serious public health concern (Bawa, 2011). Hence, one main improvement to take the

first step to this serious public health concern would be that FDA needs to start assessing

nanoparticles on a case-by-case basis to determine if general trends or themes can be identified

and whether new regulatory procedures are needed to replace the current one’s on hand (Bawa,

2011).

Conclusion

There is tremendous potential for the use of nanoparticles in cancer treatment and diagnosis,

even though many nanoparticles that have been developed are currently undergoing research,

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and still remain in clinical trials. There are already FDA-approved patented nanoparticles out in

the market, such as iron oxide nanoparticle-based magnetic resonance imaging agents (e.g.

Feridex®), which are routinely used in the clinic, as well as Doxil® (doxorubicin in long

circulating liposomes) and Abraxane® (paclitaxel in albumin nanoparticles) from the therapeutic

stand point (Amiji 2011). If there is a way of minimizing the toxicity of certain types of

oncology drugs, as well as minimizing the harmful effects that the drugs may impose on an

individual then attention should really be made on the development of these nanoparticle drug

delivery systems. Once the knowledge of these nanoparticles improve over time the greater the

chance of these nanoparticles to actually improve its efficacy and have the potential to serve as a

new means of treating cancer.

Appendices

Appendix A

Figure 1 Multifunctional nanoparticle (in this case a liposome) (1) has a stealth coating

increasing stability and decreasing plasma clearance, (2) has imaging agents allow for real time

visualization of nanoparticle biodistribution, (3) carries a payload of therapeutics, (4) actively

targets specific cells via a targeting ligand, (5) can be triggered to release its contents (Loomis et

al. 2011).

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Appendix B

Figure 2. Abraxane and Doxil are FDA-approved nanomedicines for cancer treatment on the

market today. (a) Abraxane, produced by Celgene Corp. is a nanoparticle of the drug paclitaxel

bound by the blood protein albumin. (b) Doxil is a Johnson and Johnson product composed of

crystals of the drug doxorubicin encapsulated in a lipid layer and coated with polyethylene glycol

(PEG) (Grossman and McNeil 2012).

Appendix C

Table 1. Examples of Nanomaterials in Clinical Use for Cancer Therapy

Nanomaterial Trade Name Target Adverse

Effects

Manufacturer Current

Status

Metallic

Iron Oxide NanoTherm Various

forms

Acute urinary

retention

MagForce In phase 3

clinical trials

Gold Aurimmune Various

Forms

Fever CytImmune

Sciences

In phase 2

clinical trials

Nanoshells Auroshell Head and

neck

Under

investigation

Nanospectra

Biosciences

In phase 1

clinical trials

Organic

Protein Abraxane Breast Cytopenia Abraxis

Bioscience

FDA

Approved

Liposome Doxil/Caelyx Various

forms

Hand-foot

syndrome,

stomatitis

Ortho Biotech FDA

Approved

Polymer Oncasper Acute

lymphoblastic

leukemia

Urticaria,

rash

Rhone-

Poulenc Rorer

FDA

Approved

CALAA-01 Various

forms

Mild renal

toxicity

Calando In phase 2

clinical trials

(Kim et al. 2010)

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