biomaterials for cancer therapeutics || biomaterial strategies to modulate cancer

© Woodhead Publishing Limited, 2013

417

15 Biomaterial strategies to modulate cancer

K. M. McNEELEY , J. G. LYON and R. BELLAMKONDA,

Georgia Institute of Technology, USA

DOI: 10.1533/ 9780857096760.4.417

Abstract : Biomaterials have signifi cantly enhanced current abilities to study, diagnose, and treat cancer. Biomaterials have enabled a more detailed study of cancer by improving in vitro modeling of the disease. Since biomaterials facilitate in vitro culturing of cancer cells in 3D, the in vivo tumor environment can be more accurately simulated allowing for in-depth investigations of the underlying molecular and genetic mechanisms of disease progression. Biomaterials have also been utilized to improve cancer detection methods through the development of biomaterials-based contrast agents and molecular probes specifi c for cancer. Finally, biomaterials have made a signifi cant impact in the development of therapeutics for cancer treatment. In this chapter, we demonstrate how the advancement of biomaterials has been particularly advantageous in the study, diagnosis, and treatment of cancer, as biocompatible materials have begun to play key roles in each of these areas.

Key words : cancer, biomaterials, 3D culture, diagnostic imaging, contrast agents, therapeutics, nanoparticles.

15.1 Introduction

The evolution of biomaterials has signifi cantly impacted the medical fi eld.

Biomaterials have been investigated for numerous applications and have

helped facilitate a deeper understanding of infl ammation and healing. They

have been utilized in helping replace function of organ systems (Humes,

1996), to assist healing (Maccabee et al ., 2003; Rabillard et al ., 2009), to

correct defects (Chajra et al ., 2008; Spin-Neto et al ., 2010), and in disease

prevention (Look et al ., 2010), diagnostics (Masuda et al ., 2012; Pellach et al ., 2012), and therapy (McNeeley et al ., 2009; Agarwal et al ., 2011; Deans et al ., 2012; Munson et al ., 2012). Some of the earliest biomaterials were utilized

in the skeletal system (Charnley, 1960), but as different types of biocom-

patible materials were developed, the applications have rapidly expanded.

Examples of biomaterials-based technologies can now be found for every

system within the body, and biomaterials are currently utilized to detect and

combat numerous diseases.

418 Biomaterials for cancer therapeutics


Cancer is currently a major cause of death worldwide, so it is no

surprise that the use of biomaterials has been readily investigated for the

study, diagnosis, and treatment of this disease. Biomaterials have aided in vitro modeling of cancer by enabling the culturing of cells in 3D to more

accurately simulate the in vivo tumor environment (Carletti et al ., 2011).

Through in vitro representation of cancer, we are beginning to understand

the underlying molecular and genetic mechanisms of disease progression.

Furthermore, accurate 3D in vitro characterization of tumors using biomate-

rials has aided in drug development (Horning et al ., 2008; Nirmalanandhan

et al ., 2010). Biomaterials have also been utilized to improve cancer detection

methods from enhancing available contrast agents for predictive medicine

(Karathanasis et al ., 2009b) to the development of molecular probes spe-

cifi c for cancer (Gong et al ., 2012). Biomaterials have also made signifi cant

impact in the development of therapeutics for cancer, not only in the area of

in vitro cancer modeling to facilitate drug candidate evaluation, but also in

the development of implantable drug delivery depots (Whittle et al ., 2003;

Zahedi et al ., 2012) and nano-sized carriers (McNeeley et al ., 2009; Agarwal

et al ., 2011; Munson et al ., 2012) for clinically approved treatments. Further,

use of biomaterials has also extended to facilitate thermal ablation of tumors

for improved therapeutic outcome (Glazer and Curley, 2011). In this chapter,

we demonstrate how the advancement of biomaterials has been particularly

advantageous in the study, diagnosis, and treatment of cancer, as biocompat-

ible materials have begun to play key roles in each of these areas.

15.2 Understanding cancer with biomaterials

15.2.1 2D and 3D cell culture

Much of our understanding of cancer at the cellular level has been attained

through in vitro experimentation. Initial experimentation, as well as many

current studies, has examined cancer cells grown in culture using two-dimen-

sional (2D) techniques. It has become increasingly apparent, however, that

cells grown in monolayers do not adequately replicate the in vivo tumor

environment where tumor cells are exposed to heterogeneous distributions

of oxygen, nutrients, and physical stress. In fact, this non-uniformity within

the in vivo tumor microenvironment leads to the development of cellular

heterogeneity and areas of cell damage and necrosis (Friedrich, 2003). The

advent of biomaterials has signifi cantly aided our understanding of cancer

physiology and pathogenesis by enabling in vitro examination of the disease

in a three-dimensional (3D) context. Tissue engineering principles have

driven the development of 3D culture systems based on scaffold and matrix

technologies (Hutmacher et al ., 2009). Many different types of models have

been investigated for 3D culture systems of cancer. 3D in vitro models of

Biomaterial strategies to modulate cancer 419


cancer offer a compromise between monolayer cultures and in vivo whole

animal approaches. Studies have demonstrated that 3D cultures of tumor

cells do, in fact, more accurately replicate the early stages of in vivo tumor

growth prior to angiogenesis (Kunz-Schughart et al ., 2004; Hutmacher,

2010). Notably, tumor cells grown in 3D cultures develop empty central

areas reminiscent of necrotic cores observed in vivo (Fischbach et al ., 2007).

In addition, cell replication is typically slowed compared to cells grown in

2D, thus better refl ecting the physiological growth in vivo (Gorlach et al ., 1994). Three-dimensional cultures also allow in vitro investigation of cell‒matrix interactions, which are often impossible to investigate under 2D

conditions. By more accurately representing the conditions demonstrated

by tumors in vitro in the in vitro investigations, we can obtain more reliable

conclusions on the pathogenesis of tumors and thereby improve therapeutic

outcomes.

15.2.2 Tumor spheroids

Currently, in vitro 3D culture models for cancer research include tumor

spheroids and cells grown within natural or synthetic biomaterial scaffolds.

Tumor spheroids are simple 3D clusters of cells that form due to the ten-

dency of adherent cells to aggregate when grown in suspension. These models

offer the advantage of studying cancer in 3D and enable monitoring of cell‒cell interactions, but they require rotational/agitation-based bioreactors or

specialized coatings to prevent adhesion of cells to culture fl ask surfaces

and can be diffi cult to maintain. Recently, investigators have reported an

interesting use of biomaterials to overcome these obstacles and enable an

approach for the formation of tumor spheroids that does not require spe-

cialized bioreactors. Using magnetic iron oxide nanoparticles, Souza et al . were able to magnetically levitate human glioblastoma cells to form tumor

spheroids (Souza et al ., 2010). Cells were suspended within a biomaterial

consisting of bacteriophage and gold nanoparticles that assemble into

hydrogels. Interestingly, this study demonstrated the ability to control the

shape of the tumor spheroids as well as the ability to bring separate cultures

together for studies on interactions between different cell types.

15.2.3 Biomaterials for 3D culture

Biomaterial scaffolds offer an alternative to the tumor spheroid approach.

To more accurately represent the tumor environment and enable direct

evaluation of cell–matrix interactions, biomaterial scaffolds have been uti-

lized as artifi cial extracellular matrix (ECM) to support embedded tumor

cells for in vitro 3D cultures. Over the years, one of the most widely used



biomaterials for in vitro evaluation of cancer in 3D has been Matrigel, a

matrix derived from basement membrane extract (BME) obtained from

explanted tumors initially developed over two decades ago (Streuli et al ., 1991). Matrigel is an extract obtained from the Engelbreth-Holm-Swarm

mouse sarcoma and composed chiefl y of collagen IV, laminin, entactin, and

heparin sulfate proteoglycans. While Matrigel is one of the most widely used

scaffolds for 3D in vitro cancer models and demonstrates ECM-like prop-

erties, it offers limited control over chemical and structural properties. In

addition, Matrigel is a largely undefi ned mixture of proteins and batch-to-

batch variability may negatively affect the reproducibility of experimental

outcomes. Other naturally derived biomaterials for in vitro 3D culture of

cancer cells include natural polymers such as collagen, gelatin, hyaluronate,

fi brin, fi broin, glycosaminoglycans, chitosan, alginate, silk, dextran, and

starch that may be extracted from plants, animals, or human tissues. Similar

to Matrigel, these natural polymers generally exhibit low toxicity, good bio-

compatibility, and mild gelling conditions, but may be diffi cult to process and

result in batch-to-batch variability (Carletti et al ., 2011). Synthetic biomate-

rial alternatives to naturally derived scaffolds that have been utilized for

3D cultures of tumor cells include scaffolds fabricated from metals, glasses,

polymers, and ceramics. Synthetic polymers are most commonly utilized and

tend to offer more control over reproducibility compared to natural poly-

mers. Synthetic polymers also offer the advantages of high versatility and

ease of processing, but may require harsh polymerization conditions and

are not bioactive. However, since the structural and chemical properties of

synthetic polymers can be readily altered, scaffolds may be fabricated to

mimic the principle features of natural ECM (Lee et al ., 2008). Commonly

used synthetic polymers include poly(glycolic acid) (PGA), poly(lactic acid)

(PLA), poly(lactic-co-glycolic acid) (PLGA), poly( ε -caprolactone) (PCL),

poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), poly(propylene

fumarate) (PPF), and poly(acrylic acid) (PAA).

15.2.4 Physical properties of biomaterial scaffolds

Physical properties of the biomaterial scaffold utilized for 3D culture of

tumor cells should be carefully considered. Scaffold architecture should

mimic the native tumor ECM and permit cell infi ltration and attachment

while allowing nutrient and waste permeation. Scaffold porosity, pore size

and geometry, and pore interconnectivity can have signifi cant impacts on

mass transport profi les. Additionally, these factors affect how well cells

are able to infi ltrate the biomaterial matrix. These properties are typically

dictated by the fabrication technique (Lee et al ., 2008). Fibrous structures

fabricated through electrospinning result in high surface-to-volume ratios

and mimic the fi brous network of collagen and elastin found in natural ECM,



but the resulting small pores tend to impede cell penetration. Sponge-like

matrices tend to exhibit lower surface-to-volume ratios but larger pore sizes.

Sponge-like scaffolds may be fabricated through freeze-drying, gas foam-

ing, solvent casting, or particulate leaching techniques (Lee et al ., 2008).

The composition and stiffness of the matrix also affect cell infi ltration as

well as cell signaling and behavior (Paszek et al ., 2005). Matrix stiffness can

be readily altered by varying the gel concentration or by combining poly-

mers of varied stiffness. Increased transparency of the selected biomaterial

facilitates imaging of the embedded cancer cells. Surface chemical proper-

ties, such as charge and polarity, of the biomaterial dictate adhesion and

spreading of the tumor cells within the scaffold. Scaffold surface charge dic-

tates the amount of proteins that adsorb, which typically correlates with

the tendency of cells to adhere to the matrix (Allen et al ., 2006). Chemical

modifi cation of surface properties offers the possibility for enhancement of

cell‒matrix interactions. For example, studies on glioma cells demonstrated

increased matrix adhesion when hyaluronic acid gels were functionalized

with Arg-Gly-Asp (RGD) peptides (Ananthanarayanan et al ., 2011). RGD

density also had a signifi cant impact on cytoskeletal organization, resulting

in increased cell spreading and decreased circularity.

Studies have repeatedly demonstrated numerous differences in cells

grown under 2D vs 3D conditions, including differences in cell differentia-

tion (Chen et al ., 2012), drug metabolism (Nirmalanandhan et al ., 2010),

viability (Li et al ., 2008), gene and protein expression levels (Gaedtke et al ., 2007; Souza et al ., 2010), cell morphology (Kraning-Rush et al ., 2011), pro-

liferation (Carey et al ., 2012), and response to applied stimuli (Sowa et al ., 2010). These differences emphasize the necessity for performing in vitro

cancer experiments under 3D culture conditions. For example, cancer drugs

that work on cell‒matrix interactions may go undetected if cells are cul-

tured under 2D conditions for chemotherapeutic screening studies. In fact,

one group evaluated a variety of lung cancer drugs and found that over 70%

of the drugs tested demonstrated confl icting responses from cells grown

under 2D vs 3D culture conditions (Nirmalanandhan et al ., 2010). Due to

the poor predictive value of 2D in vitro assays for cancer drug development,

investigators have recognized the need for 3D model development using

biomaterials and an increasing number of studies are utilizing them for in vitro testing (Horning et al ., 2008; Harma et al ., 2010).

15.2.5 Cell‒matrix interactions

Investigators have long been trying to gain a better understanding of

tumor proliferation and invasion at the cellular level. When investigating

the invasive nature of tumors, the impact of the tumor on its surround-

ing microenvironment cannot be neglected. For in vitro studies aimed at



investigating this phenomenon, biomaterials must often be utilized to

model the surrounding tumor microenvironment. Cell invasion assays rou-

tinely use a Boyden chamber design where a porous membrane is coated

with a biomaterial such as Matrigel to represent the ECM (Kleinman and

Jacob, 2001). Cell migration through the biomaterial is assessed to deter-

mine the invasive capacity of the cells after seeding the cells on top of the

gel. Alternatively, cell invasion may be investigated by seeding tumor cells

or tumor spheroids within biomaterials as a true 3D culture system to inves-

tigate cell–matrix interactions. For example, Gordon et al . used a 3D ECM

Matrigel in vitro assay to demonstrate how the volumetric expansion of a

brain tumor spheroid grown within a collagen gel generates pressures on

the surrounding environment that cause outward radial displacement of the

surrounding matrix; however, at the same time, a portion of the surround-

ing material near the peripherally-located invasive tumor cells experiences

inward traction forces (Gordon et al ., 2003).

Kaufman et al . further examined the mechanical aspects of tumor cell migra-

tion using collagen gels of various concentrations to determine the effect of

matrix stiffness on the expansion of glioblastoma spheroids (Kaufman et al ., 2005). They observed that tumor cells are heavily affected by cell‒matrix

interactions, and that the specifi c interactions between tumor cells and sur-

rounding collagen fi bers drive invasion, thereby concluding that stiffer gels

promote tumor cell invasion presumably due to an increased availability of

collagen fi bers for integrin attachment. Indeed, studies using collagen gels to

investigate cell‒matrix interactions have shown that the mechanical proper-

ties of the surrounding matrix infl uence expression levels of specifi c molecules

directly linked to tumor cell invasive potential (Hegedus et al ., 2006).

Ulrich et al . developed a hybrid gel biomaterial that allows modifi cation

of collagen gel stiffness with minimal effect on the gelation kinetics, fi ber

diameter, porosity, and integrin binding sites (Ulrich et al ., 2010). This was

accomplished by incorporating various amounts of agarose into collagen gel

scaffolds to enable tuning of the ECM biophysical properties without alter-

ing the collagen content. By maintaining the collagen fi ber diameter and

number of integrin binding sites with this hybrid biomaterial, they were able

to observe how increasing gel stiffness alone actually inhibits tumor cell

invasion, due to steric hindrance and decreased gel porosity. This result was

in contrast to what they observed with polyacrylamide gels (Ulrich et al ., 2009), which stresses the importance of cell‒matrix interactions on motil-

ity. Carey et al . used collagen gels of defi ned concentration and thickness to

demonstrate how tumor cell morphology and migration is dependent on

gel microarchitecture, while proliferation is affected by gel stiffness (Carey

et al ., 2012). These results emphasize that while there are distinct differences

in cellular behavior observed between cells grown under 2D and 3D condi-

tions, the specifi c architecture of the substrate or matrix utilized to culture the



cells in 3D directly affects the cellular behavior. Biomaterials utilized for 3D

culture of tumor cells have aided investigations of cell–matrix interactions

that have served to advance our understanding of how invading tumor cells

interact with surrounding ECM.

For studies aimed at investigating cancer cell malignancy and metastatic

potential, there is evidence to suggest that the use of 3D cultures promotes

overexpression of epithelial to mesenchymal transition (EMT) markers

associated with increased metastatic potential. Chen et al . demonstrated ele-

vated expression levels of EMT markers as well as pro-angiogenic growth

factors and matrix metalloproteinases (MMP) involved in ECM degrada-

tion for tumor cell invasion when breast cancer cells were grown in collagen

scaffolds (Chen et al ., 2012). Interestingly, they also reported a signifi cant

increase in the number of cells expressing cancer stem cell markers when

these cells were grown under 3D conditions versus 2D cultures. These results

indicate that 3D structures enhance the malignant phenotypes of cancer

cells to better replicate in vivo tumors.

15.2.6 Advanced 3D models

Recently, investigators have started using increasingly sophisticated

3D models with biomaterials. For example, Raja et al . developed a

chemotaxis device using a UV-curable blend of poly(ethylene glycol) dia-

crylate/poly(ethylene glycol) monomethyl ether methacrylate (PEGDA /

PEGMA) hydrogel releasing epidermal growth factor (EGF) to study

mammary carcinoma cell migration in collagen gels (Raja et al ., 2010).

This versatile chemotaxis device should prove to be useful for probing

the chemotactic potential of cancer cells using collagen as a biomate-

rial scaffold. A system using electrospun polycaprolactone/collagen to

mimic the fi brous nature of tumor ECM was developed by Szot et al . (2011). Cells grown on these gels demonstrated partial infi ltration and

steady proliferation, adhesion, and normal morphology. The investiga-

tors acknowledged that increased gel porosity must be engineered into

the scaffolds to promote cell infi ltration. They also suggest co-culture of

tumor cells with endothelial cells to stimulate angiogenesis. Others have

used collagen to develop elaborate 3D human skin reconstruct models to

study melanoma (Li et al ., 2011). Models have been fabricated by embed-

ding fi broblasts within collagen to create a dermal layer. Keratinocytes

and melanoma cells were seeded on top of this gel layer. Keratinocytes

remained at the top of the gel and formed the epidermis, which was sepa-

rated from the dermis by a functional basement membrane. As is typical

in vivo , the melanoma cells localized as clusters within the epidermal

region and invaded into the dermis through the basement membrane.



Using collagen as a scaffold biomaterial, this model presents an ideal pre-

clinical tool to investigate melanoma and bridges, to a great extent, the

gap between in vitro and in vivo testing.

15.2.7 Angiogenesis

Finally, biomaterials have been utilized to enable the study of tumor angio-

genesis in vitro . In vivo , it has been established that tumor angiogenesis is

driven by hypoxia-induced overproduction of pro-angiogenic factors. Cells

grown in 2D do not typically develop hypoxic regions since the cellular

monolayer is constantly exposed to the nutrient rich media across which

gas exchange readily occurs. Tissue-engineered 3D tumor models using

biomaterials, however, enable the development of hypoxic regions by rec-

reating the heterogeneous tumor-inherent cell microenvironment in vitro .

It is the presence of these hypoxic regions that drive tumor vascularization

and make in vitro evaluation of angiogenesis possible. Biomaterials such

as collagen gels have been utilized for over 20 years for in vitro evalua-

tion of angiogenesis (Montesano et al ., 1986). Only recently, however, have

models been developed that are capable of capturing the aspects of tumor

sprouting angiogenesis. Using collagen gels, sprouting angiogenesis of a

breast cancer cell line has been investigated in vitro (Correa De Sampaio

et al ., 2012). Human breast cancer cell spheroids were implanted within

collagen gels along with endothelial cells and fi broblasts for a 3D spheroid

co-culture and sprouting assay. Using this system, the investigators were

able to test a variety of anti-angiogenic agents and obtained results that

more closely mimicked results from human clinical trials; whereas simpler

in vitro models have often led to confl icting outcomes. This system, there-

fore, is more aptly suited for predictive testing of angiogenic inhibitors

slated for clinical use.

15.2.8 Conclusion

Numerous properties of cancer have been studied using 3D culture models,

and many of these studies would not be possible without the development

of biomaterials to enable 3D representation of the tumor environment in vitro . The use of biomaterials for 3D in vitro cultures of tumor cells has

facilitated the expansion of our understanding of cancer in regards to

drug development, tumor response to surrounding microenvironment and

applied stimuli, signaling pathways, invasive propensities, angiogenesis, and

metastasis. By providing a scaffolding to mimic the natural tumor microen-

vironment, these properties could be investigated at the cellular level under

conditions that more accurately represent the in vivo scenario. Ultimately,



these models bridge the gap between 2D in vitro models and whole animal

studies and enable conclusions that are more applicable to the clinical

setting.

15.3 Molecular markers for cancer

Biomaterials have recently come to the forefront of cancer diagnostic

research. By altering the properties of traditional diagnostic agents, biom-

aterials are often capable of improving current diagnostic capabilities for

cancer. Early diagnosis of cancer greatly contributes to improved prognosis.

Currently, cancer diagnosis is primarily based on volumetric and morpho-

logic criteria obtained from non-invasive imaging techniques and histological

grading of biopsy specimen or fi ne needle aspirations. Standard imaging

methods such as computed tomography (CT), magnetic resonance imaging

(MRI), positron emission tomography (PET), and single-photon emission

tomography (SPECT), however, suffer from spatial resolution limitations.

Biomaterials enable unique approaches to cancer diagnostics. Most nota-

bly, nanoparticles composed from biomaterials offer improved diagnostic

capabilities due to their ability to favorably alter the pharmacokinetics of

contrast agents utilized for tumor imaging and detection. Additionally, the

properties of these agents can be fi nely tuned to promote desirable interac-

tions at the cellular level enabling targeted delivery to specifi c cell types. The

large surface area of nanoparticles to be utilized for conjugation of targeting

agents or specifi c coatings makes this functionality possible. Furthermore,

these vehicles can be designed to carry a diverse selection of detection

agents or probes for molecular, cellular, and in vivo imaging. Here, we pres-

ent a few examples of biomaterials that have been utilized for improved

cancer detection.

15.3.1 Quantum dots

It is important for diagnostic tests to be reliable, sensitive, and reproducible.

It is practical, therefore, to use fl uorescent biomaterials in diagnostics to

detect specifi c bimolecular interactions. Fluorophores provide a non-inva-

sive method to obtain sensitive and specifi c images with adequate spatial

resolution (Resch-Genger et al ., 2008). The size, biocompatibility, and chem-

ical makeup of a fl uorophore dictate the resulting imaging and detection

capabilities. Currently, there are three predominant groups of fl uorophores

that are being investigated. Each of them is used for labeling single mol-

ecules. These groups are fl uorescent proteins, organic dyes, and quantum

dots (Resch-Genger et al ., 2008; Pinaud et al ., 2010). Quantum dots are

nanometer sized (2–10 nm) crystalline biomaterials that function as semi-

conductors. Semiconductor colloid research began in the 1960s, and almost



two decades later, quantum dots were introduced by Ekimov et al . (Ekimov

and Onushchenko, 1981). Quantum dots are typically developed with cad-

mium, selenium, or tellurium coated with zinc sulfi de. The fl uorescence

emission wavelength is correlated to the particle size, which is readily tun-

able. Quantum dots are unique because they are small, remarkably bright,

resistant to photobleaching, and are able to be excited at a single wave-

length resulting in intermittent fl uorescent emission producing a blinking

phenomenon. Recent advances in quantum dot synthesis have resulted in

particles with emission wavelengths in the near-infrared (NIR) range. NIR

is capable of penetrating living tissue making in vivo imaging with these

particles a reality. Designing a quantum dot consists of three basic steps,

namely, particle synthesis, external coating for biocompatibility, and surface

modifi cation for target specifi city. Tumor targeting capability is conferred

with the addition of antibodies, peptides, or small molecules. Investigators

have demonstrated the ability to target and detect tumors using quantum

dots. One group has shown the ability to target brain tumors in rats with

quantum dots. At low doses, the particles were detected in the liver and

spleen, the primary routes of clearance from the bloodstream; however, at

higher doses, the particles colocalized with the experimental gliomas that

could then be imaged non-invasively (Jackson et al ., 2007). Gao et al . have

demonstrated the use of targeting agents to promote the uptake of quantum

dots by tumors (Gao et al ., 2004). Quantum dots were tagged with antibodies

specifi c for prostate specifi c membrane antigen. These particles accumulated

within human prostate cancers implanted in nude mice that could be visu-

alized non-invasively after intravenous injection of the particles. Possible

limitations to the use of quantum dots that must be examined further prior

to their use in the clinic include potential toxicity due to heavy metal con-

tent and the need for specialized imaging equipment for detection.

15.3.2 Nanocarriers for contrast agents

While quantum dots have proven to be useful pre-clinically for fl uores-

cent and NIR imaging of cancer and demonstrate the potential for use in

the clinic, alternative biomaterials can be utilized to encapsulate contrast

agents that are already clinically approved for diagnostic imaging of cancer.

Nanocarriers that are most commonly studied for this application include

polymeric nanoparticles, liposomes, and micelles. Polymeric nanoparticles

are produced from natural or artifi cial polymers and range in size from 10

to 1000 nm. They can be formulated directly from polymers or from the

polymerization of monomers. The most commonly utilized biomaterials for

polymeric nanoparticles include PLGA (Lin et al ., 2005; Yemisci et al ., 2006),

PLA (Zhang and Feng, 2006), PCL (Shenoy and Amiji, 2005; Devalapally

et al ., 2007), chitosan (Xu and Du, 2003; Qi et al ., 2007), and human serum



albumin (Dreis et al ., 2007). Nanospheres are spherical in shape and com-

posed of a polymer matrix. Contrast agents may be entrapped, encapsulated,

or attached to the nanospheres for delivery to target sites. Nanocapsules

are hollow spheres fabricated from natural or artifi cial polymers. The hol-

low central core may be utilized for contrast agent encapsulation (Parveen

and Sahoo, 2008). Liposomes are closed spherical nanoscale vesicles with

an aqueous core surrounded by a phospholipid bilayer. Liposomes may be

composed from a variety of phospholipids, the most common being either

natural (egg or soy) or synthetic phosphocholine. The phase transition

temperature of the phospholipids dictates the stability of the fi nal particle.

Additionally, cholesterol is often incorporated into liposomes to enhance

physical stability. Liposomes are formed by the spontaneous association of

amphiphilic phospholipids in an aqueous environment due to hydrophobic

interactions. Afterwards, they are usually sized down to a 50–200 nm diame-

ter via extrusion or sonication for in vivo applications. Micelles are typically

smaller in size (10–100 nm) compared to liposomes and are formed in a

similar manner where the driving force for formation is hydrophobic inter-

actions causing the non-polar segments of copolymer molecules to form the

micellar core and the relatively polar segments to form the exterior. For

this reason, micelles are more suited for encapsulating hydrophobic com-

pounds, while liposomes are capable of encapsulating hydrophilic agents

within the internal core or hydrophobic compounds within the lipid bilayer.

The size of micelles depends on the copolymer length, molecular weight,

and relative proportion of hydrophobic and hydrophilic segments, which

all determine how well the copolymers pack within the micelle. The most

commonly studied biomaterials used for the hydrophobic segment of copo-

lymers comprising micelles are polyethers, polyesters, and polyamides, while

the most commonly used polymer for the hydrophilic corona of micelles is

PEG (Kwon, 2003).

For all of these nanocarriers, PEG coatings are often utilized to prolong

circulation within the bloodstream. PEG serves as an effi cient steric barrier

between the nanocarriers and plasma proteins responsible for removing for-

eign particles from the bloodstream promoting prolonged circulation times.

Indeed, micelles using PEG in the corona have exhibited plasma half-lives of

18 h after intravenous administration (Yamamoto et al ., 2001). For tumor diag-

nostics, prolonged circulation time of contrast agents within nanocarriers is

advantageous because it results in passive accumulation of the agents within

solid tumors and increased contrast compared to normal tissue. Inherently,

tumor blood vessels are marked by compromised endothelial junctions with

pores ranging from 100 to 780 nm in size (Maruyama et al ., 1997; Siwak

et al ., 2002). Therefore, prolonged circulation of liposomes in the blood-

stream and repeated passage through the tumor microvascular bed allows

for sustained accumulation of nanocarriers at the tumor site. This effect has



been termed the enhanced permeability and retention (EPR) effect. Many

studies have demonstrated the ability to visualize tumors using nanocarrier

encapsulated contrast agents that accumulate within tumors via the EPR

effect. In fact, using liposomally encapsulated CT contrast agents, our group

has shown how the accumulation of liposomal nanocarriers within tumors

is directly correlated to the degree of vascular leakiness exhibited by tumors

and dictated by expression of vascular endothelial growth factor (VEGF)

and vascular endothelial growth factor receptor (VEGFR) (Karathanasis

et al ., 2009a). Through CT imaging studies utilizing intravenously delivered

liposomal contrast agent, we were able to ascertain the tumor vascular sta-

tus non-invasively and use this data to predict which tumors would respond

better to subsequent treatment with liposomal chemotherapeutics. To fur-

ther improve on tumor accumulation achieved via EPR, nanocarriers may

be coated with agents such as antibodies, peptides, or receptor ligands that

specifi cally bind tumor cells. Many groups have reported successful target-

ing of contrast agents to tumors using targeted nanocarriers. For example,

Sun et al . demonstrated folic acid mediated targeting to a xenograft breast

tumor in mice using micelles carrying both a magnetically resonant (MR)

contrast agent and a NIR dye (Sun et al ., 2011). Tumor contrast was sig-

nifi cantly enhanced using this nanocarrier MR contrast agent delivered to

tumors proving that these micelles offer a promising approach for cancer

detection and diagnosis.

15.3.3 Super paramagnetic iron oxide nanoparticles (SPIONs)

SPIONs are composed of an iron oxide core surrounded by a hydrophilic

polymer coating and are utilized as contrast agents for MR imaging. Coatings

may be fabricated from dextran, starch, alginate, PLGA, and PEG. These

coatings impart stability and biocompatibility, as well as the ability to evade

the immune system and prolong circulation time. As with contrast agent

nanocarriers, prolonged circulation promotes accumulation of SPIO nano-

particles within tumors due to the EPR effect. Particles range in size from

5–300 nm in diameter. The paramagnetic properties of iron oxide enable

it to shorten MR relaxation times to generate image contrast at the site of

accumulation; however, unlike traditional MR contrast agents such as gado-

linium, iron oxide is a negative enhancer that reduces the signal at the target

site. Many of these particles have been approved for clinical use and studies

have demonstrated their ability to detect tumors smaller than the current

detection limit of conventional MRI (Harisinghani et al ., 2003). Additionally,

these particles may be specifi cally targeted to tumors using targeting ligands.

For example, it has been shown that greater tumor contrast can be achieved

with SPIONs after conjugating folate to the particles as a tumor targeting



ligand (Chen et al ., 2008). This group used 30 nm PEG coated SPIONs to

demonstrate how the attachment of folate signifi cantly enhances MR con-

trast within a human nasopharyngeal epidermal carcinoma tumor model

that overexpresses the folate receptor. Delivery to the tumor with folate

resulted in elevated contrast and improved detection making these particles

a viable option for MR imaging of tumors.

15.3.4 Conclusion

By enhancing tumor imaging, biomaterial-based contrast agents offer

the possibility of signifi cantly improving the current detection limits for

tumors. Since there is a correlation between early detection of tumors and

improved prognosis, enhancing current tumor imaging approaches is criti-

cal. Biomaterials have aided on this objective by offering new and improved

agents for imaging tumors. Additionally, biomaterials have been utilized to

improve upon currently approved contrast agents by enhancing the ability to

accumulate within tumors after intravenous administration. By prolonging

contrast agent residence time in the bloodstream, biomaterials have allowed

for increased contrast agent accumulation within tumors. Also, biomaterials

have enabled the incorporation of tumor targeting agents to promote the

specifi c targeting of imaging agents to tumors allowing for improved con-

trast and detection (Walker et al., 1980; Pfeiffer and Gard, 1988).

15.4 Biomaterials for cancer therapy

Innovations in biomaterial engineering also yield potential innovations

for cancer therapy. Traditionally, treatment options for cancers have been

limited to surgical resection of primary tumor mass followed by adjuvant

chemotherapy and fractionated radiotherapy in an attempt to toxify the

remaining cancerous tissues and possibly prevent recurrence. Work in the

biomaterials fi eld has not only been able to enhance the effi cacy of these

standard therapies, but also to offer novel forms of treatment.

15.4.1 Biomaterials for systemic and local drug delivery

Enabling more effective chemotherapy and, in general, drug delivery, has

been a major focus in the development of biomaterial systems. Much of

what was discussed above with respect to diagnostic particle delivery holds

true for therapeutic drug delivery systems, in that the use of biomaterial

substrates enables manipulation of the pharmacokinetics of the payload

drug. Chemotherapeutic drugs are typically administered intravenously,

which leads to limited circulation times, limited targeting and penetration



of cancerous tissues, excludes the use of water-insoluble drugs, and effective

doses can lead to toxic effects in healthy tissues, particularly blood-fi ltrating

organs. It is now possible to simultaneously bypass many of these concerns

through biomaterial-based drug delivery systems while still delivering treat-

ments intravenously.

The primary component of a biomaterial drug delivery system is the basic

substrate material. Available materials are diverse and range from natural

and synthetic polymers (e.g., PLGA (Lin et al ., 2005; Yemisci et al ., 2006;

Kocbek et al ., 2007), PLA (Zhang and Feng, 2006), PCL (Shenoy and Amiji,

2005; Devalapally et al ., 2007), chitosan (Xu and Du, 2003; Qi et al ., 2007)), to

animal and plant proteins (e.g., gelatin (Leo et al ., 1997; Okino et al ., 2003; Yeh

et al ., 2005), collagen (Davidson et al ., 1995), albumin (Dreis et al ., 2007), lec-

tins (Lehr, 2000; Bies et al ., 2004)), to metals (e.g., gold (Agarwal et al ., 2011;

Glazer and Curley, 2011), iron (Harisinghani et al ., 2003; Souza et al ., 2010))

to lipids (Maruyama et al ., 1997; Siwak et al ., 2002; Agarwal et al ., 2011) or

carbon (Glazer and Curley, 2011). Given a particular material substrate, deliv-

ery systems can be developed in a variety of forms. In the case of systemic

delivery this is typically a nano- or micro-particle system where the drug is

either encapsulated within or conjugated to the carrier substrate including

but not limited to: micelles (Shuai et al ., 2004; Nasongkla et al ., 2006), vesicles

(Farokhzad et al ., 2006), nanogels (Dickerson et al ., 2010), liposomes (Puri

et al ., 2008; Pradhan et al ., 2010; Munson et al ., 2012), metal-based nanopar-

ticles (Weinstein et al ., 2010), and carbon nanotubes (Liu et al ., 2008; Bhirde

et al ., 2009). For localized delivery, typically larger biomaterial constructs are

used, such as wafers (Brem et al ., 1995; Westphal et al ., 2003), microspheres

(Yemisci et al ., 2006; Mazzitelli et al ., 2011), hydrogels (Ruel-Gariepy et al ., 2004), and fi lm composites (Liu et al ., 2010b). Multiple substrates and form

factor geometries can also be combined for use in the same system to add

even more design complexity (e.g., Ashley et al ., (2011)).

The variety and fl exibility of biomaterial substrate choice affords many

new opportunities for chemotherapeutics. For instance, tumor necrosis fac-

tor (TNF), a potent pro-apoptotic chemotherapeutic, was once deemed too

toxic to be clinically viable. However, by conjugating TNF to PEGylated

gold nanoparticles, Libutti et al ., were able to safely administer three times

the previous dosage, and now that particular drug formulation is clinically

available as Aurimune (Libutti et al ., 2010). Another common chemother-

apeutic that has been improved by biomaterials is the DNA-intercalating

agent, doxorubicin. When administered as a free drug, doxorubicin can

cause serious damage to cardiac muscles; however, this negative impact to

cardiac tissue is signifi cantly reduced when it is encapsulated in liposome

nanoparticles (as Doxil) (O’Brien et al ., 2004).

An example of a local delivery system is the Gliadel wafer, a therapy that

is clinically available for treatment of malignant gliomas (Brem et al ., 1995;



Westphal et al ., 2003). A Gliadel wafer is formulated as a 1.4 cm diameter,

1.0 mm thick disk of polyanhydride polymer (at a 20/80 ratio of poly-car-

boxyphenoxypropoane and sebacic acid, respectively) that is loaded with

carmustine, a chemotherapeutic alkylating agent. The wafer is typically

implanted into a resection site, wherein the controlled release of carmus-

tine limits the survival of unresected cancerous tissues and can prevent

recurrence. By using this controlled delivery system for carmustine rather

than injected delivery, the drug’s negative side effects, particularly its ability

to severely diminish the bone marrow-residing blood cell population, are

largely ameliorated.

The ability to improve drug solubility is also an important benefi t of a bio-

material system. Paclitaxel, a mitotic inhibitor that is clinically available for

treatment of ovarian, breast, and lung cancers, is fairly water-insoluble, although

it can be delivered in a stabilized form in castor oil (as Taxol) (Runowicz

et al ., 1993). However, when paclitaxel is solubilized by encapsulation in

blood serum albumin (as Abraxane) (Miele et al., 2009), it yields increased

therapeutic effi cacy and reduced toxicity when compared to the non-biomate-

rial-based Taxol. Paclitaxel is also available for localized treatment of tumors

as OncoGel. OncoGel is made by encapsulating paclitaxel in a thermosensitive

gel comprised of the tri-block copolymer, PLGA-PEG-PLGA. When injected

intratumorally, the gel undergoes a reversible thermal gelation and will pro-

ceed to degrade for as long as 8 week post-injection, leading to the controlled

elution of paclitaxel at the tumor site (Zentner et al ., 2001).

Importantly, many of the systems discussed in this section can be applied

in parallel, and single system payloads are not merely limited to single drugs

but can be used to deliver multi-drug cocktails. Encapsulation systems also

enable new delivery payloads beyond traditional chemotherapy, allowing

delivery of water-insoluble drugs (as discussed for paclitaxel), DNA (Kievit

et al ., 2010), small interfering (RNA) (siRNA) (Veiseh et al ., 2010), and even

therapeutic stem cells that secrete tumor-selective, pro-apoptotic factors

(Kauer et al ., 2012). Further, delivery particles can be co-loaded with both

drug(s) and diagnostic marker(s) (e.g. gadolinium, superparamagnetic iron

oxide), enabling theranostic delivery constructs, i.e., simultaneous diagnostic

and therapy (Kievit and Zhang, 2011; Shi et al ., 2011; Liu and Zhang, 2012).

15.4.2 Enhancing biomaterials for cancer drug delivery

Beyond providing the basis for further delivery system modifi cations, an

important role of the delivery substrate is to control the release mechan-

ics of the drug. This can involve the inherent biodegradability of the

encapsulation medium, material geometry, and size, or the inclusion of a

stimulus-triggered release mechanism. In particular, the use of stimulus-trig-

gered drug release has the ability to thwart some of the major limitations of



standard chemotherapy treatments with regard to limiting toxic side effects

in healthy tissues. These trigger mechanisms may either be driven by the

endogenous biology of the tumor microenvironment, or by an exogenous or

non-invasive external stimulus. Typical endogenous triggers are pH- (Shim

et al ., 2007; Yue et al ., 2011) or enzyme-responsiveness (Meers, 2001) and

there are a variety of biomaterials that respond to the application of an

externally applied stimuli: e.g., thermal (Shim et al ., 2007; McNeeley et al ., 2009), radiofrequency (Peiris et al ., 2012), radiation (Schroeder et al ., 2012),

or ultrasound (Schroeder et al ., 2009). Again, as with most aspects of these

biomaterial-based delivery systems, these features that trigger release in

response to a stimulus may be combined for added complexity. For instance,

Agarwal et al ., combined administration of both radiation-responsive gold

nanoparticles with thermosensitive liposomes loaded with doxorubicin for

treatment of glioma (Agarwal et al ., 2011). In this case, gold nanoparticles

were designed such that administration of a near-infrared stimulation would

elicit a localized photothermal hyperthermia. Thus, because both the gold

nanoparticles and liposomes would accumulate in the leaky tumor vas-

culature (via EPR effect), the localized heating would trigger release of

doxorubicin from the thermosensitive liposomes. This triggered rapid and

local release of drug was shown, in a murine model of glioma, to increase

tumor-site apoptosis, thus enhancing the effi cacy of liposomally-delivered

doxorubicin compared to liposomal-encapsulation alone.

As discussed for diagnostic delivery systems, the drug-carrying system

may be further modifi ed to enable improved biocompatibility, immune

system evasion, and enhanced tissue targeting. Further modifi cations may

be made in order to selectively target cancerous tissues and increase the

likelihood of endocytosis of the drug payload. This is particularly impor-

tant for increasing the available treatment dosage of a drug that otherwise

would lead to poor uptake into tumor tissues and is yet another example

of how biomaterial-based therapies can mitigate issues of toxicity in che-

motherapy. Numerous targeting moieties have been utilized to enable site

specifi c targeting of over- or selectively-expressed molecules on cancer cells

including (but most defi nitely not limited to): DNA-based aptamers to tar-

get Nucleolin (Cao et al ., 2009), affi body targeting of Human Epidermal

Growth Factor-2 (Alexis et al ., 2008), neovascular integrin-targeting peptides

(Danhier et al ., 2009), and folate (Park et al ., 2005) or vitamin H (biotin) (Na

et al ., 2003) targeting of their respective receptors. Targeting modifi cations

not only improve carrier homing to the site of tumors and selective target-

ing, but also contribute in achieving endocytosis in targeted cells. Probably

the most important caveat to using these targeting molecules is that it is rare

to achieve perfect selection of target vs non-target tissues, as many of these

surface markers are endogenously expressed on other cell types. Further,

some targeting ligands can be prone to non-specifi c binding.



One such biomaterial-based strategy for enhancing drug targeting was

presented by von Maltzahn et al ., wherein they used biomaterials to com-

municate across an endogenous signaling pathway in order to amplify

targeting to the tumor site (von Maltzahn et al ., 2011). This scheme utilized

NIR-responsive gold nanorods, which as discussed previously, accumulate

at the leaky vasculature of tumors via EPR. It is important to realize, how-

ever, that less than 5% of the total administered nanorods are found at the

tumor sites. When exposed to externally applied NIR radiation, these par-

ticles oscillate and, through heat-induced disruption of tumor vasculature,

locally activate the coagulation cascade. By using a secondary nanoparti-

cle (containing either drug or diagnostic marker) that is targeted to one

of two amplifi ed downstream signals of this cascade (polymerized fi brin or

transglutaminase FXIII) it was shown that local accumulation of targeted

particles could be amplifi ed over 40 times relative to controls.

While combining multiple surface conjugations can enhance effi ciency

and specifi city of drug delivery, when making multiple modifi cations to

biomaterial systems, one must consider potential competing interactions,

and much work is devoted to optimizing such systems to achieve a balance

of effects. For example, as mentioned with respect to diagnostic systems, a

common way to camoufl age a biomaterial from the immune system is to

coat the substrate with PEG chains, although this can limit the ability for

a platform to effi ciently interact with cancerous tissues due to masking of

the targeting ligand with the relatively large PEG molecules. In response to

this issue, McNeeley et al ., developed a system that makes use of a stimulus

responsive PEG coating, such that this masking effect can be turned off

after the particles have passively accumulated at the tumor site (again, by

EPR effect) (McNeeley et al ., 2009). In this design, the surface of a lipo-

somal nanocarrier was conjugated with a targeting ligand (folate) and PEG.

However, a thiol-cleavable disulfi de bridge was inserted between the PEG

chains and lipid bilayer, such that after systemic delivery of cysteine, the

PEG chains would be cleaved, unmasking the folate and thus enabling

folate-receptor-mediated targeting. It was shown that by utilizing a cleav-

able immunocamoufl age molecule, circulation times were uncompromised

and interaction with the receptors was enabled.

Biomaterial delivery systems can also be modifi ed to enable new ways to

deliver more effi ciently and penetrate otherwise impenetrable tissues. Some

of the biomaterial-enabled strategies for targeting or penetration in hard-to-

penetrate tissues include: MRI-guided magnetic nanoparticles (Alexiou et al ., 2006; Mejias et al ., 2011; Yue et al ., 2011), ultrasonic disruption of tissue bar-

riers with microbubbles (Liu et al ., 2010a), convection-enhanced delivery of

nanocarriers (Allard et al ., 2009), and hijacking endogenous transport mecha-

nisms (Ulbrich et al ., 2009). Of these technologies, those that allow breach of

the blood-brain barrier (BBB) are of particular interest, as one of the major



impediments to treating brain cancers is the inability to allow transport of

substances larger than approximately 60 nm. Nance et al ., have recently shown

that a dense coating of PEG on the surface of a nanocarrier allows diffusion

across the BBB for particle sizes up to 114 nm, thus even mere optimization

of current biomaterial constructs may be suffi cient for improving treatment

effi cacy across biological boundaries (Nance et al ., 2012).

15.4.3 Alternative and emerging strategies for treating cancer with biomaterials

While we have discussed in considerable depth how traditional chemo-

therapy can be enhanced with biomaterials, there exist many alternative

strategies for treating cancer with biomaterials that do not represent

traditional drug delivery paradigms.

Enhancing surgical intervention

Indirectly, improved diagnostics enable better surgical intervention. Above, we

considered biomaterial systems that provide diagnostic benefi t for the track-

ing and detection of cancers in the body. These systems have also been used

for the benefi t of demarcating tumor boundaries before or during surgery

(with intraoperative MRI) in order to enhance the ability of a surgeon to visu-

ally determine when either suffi cient tumor has been removed, or to delineate

when the resection begins to encroach on the surrounding, possibly sensitive,

healthy tissues. Biomaterials have also been instrumental in the development

of tissue engineering technologies for the restoration of tissue lesions, bone,

and in some instances, whole organs (see reviews (Lutolf and Hubbell, 2005;

Place et al ., 2009; Badylak et al ., 2011)). The availability of these technologies

is especially important when considering situations where tumor resection

causes a large defi cit in healthy tissue or where without replacement tissue,

the survival risk of the patient would rule out surgery as a viable option.

Enhancing radiotherapy

Radiotherapy typically consists of either the administration of an exter-

nally applied radiation beam or brachytherapy, the local implantation of a

radioactive material in tumor tissue, both of which can be enhanced using

biomaterials. Radiofrequency responsive particles, such as ceramic micro-

spheres (Kawashita et al ., 2003), or gold (Hainfeld et al ., 2004) or iron oxide

(Maier-Hauff et al ., 2011) nanoparticles can be used to enhance the effect

of externally applied radioactive, or to allow for smaller effective radiation

doses, which is particularly important for reaching deep-seated cancers. For

enhancement of brachytherapy, Azab et al . have shown that using implant-

able biodegradable chitosan hydrogel to control the elution of radioactive



material away from the treatment site into the bloodstream, coupled with

dialysis, removes the need for radioactive source removal, which would nor-

mally require a secondary surgery (Azab et al ., 2006).

Hyperthermia

An alternate use of NIR-responsive or ferromagnetic nanoparticles is to

use their induced heating effects directly to thermally ablate tumors. For

example, Auroshell, currently in clinical trials for head and neck cancer, is a

NIR-responsive nanoparticle with a gold shell and silica core that thermally

destroys tumor tissue upon external application of NIR laser light.

Immunotherapy

Traditional immunotherapy has been used in order to suppress an undesired

immune response; however, in cancer immunotherapy the goal/challenge

is to activate the immune system in order to suppress tumor growth. Many

of the drug delivery concepts are relevant here, as the goal is to provide a

tumor microenvironment-localized (i.e., targeted), sustained (i.e., controlled

release) activation to ensure that the response is limited to cancerous tissues

and that a suffi cient tumor-suppressive immune response is achieved. For

instance, Park et al . used delivery of immunostimulatory molecules (interleu-

kin-2 and transforming growth factor beta (TGF - β ) inhibitor) in nanoscale

liposomes with a biodegradable polymer core to show increased animal

survival and delayed tumor growth in a murine model of metastatic mela-

noma (Park et al ., 2012). Other emerging strategies for using biomaterials in

cancer immunotherapy include: nanoparticle-mediated cancer vaccination

(Peek et al ., 2008), suppression of regulatory T-cells with biomaterial-based

‘danger’-signal mimicking adjuvants (Hubbell et al ., 2009), and implantable

three-dimensional immunoregulatory niches (Hori et al ., 2009).

15.5 Conclusion

Above we have discussed many ways in which traditional drug delivery

formulations can be used as cancer therapies, as well as several emerging

biomaterial-based alternative treatment strategies. Additionally, we have

presented how biomaterials have provided a means by which tumors can be

more accurately represented in vitro allowing for more reliable studies aimed

at promoting our further understanding of cancer and facilitating treatment

development. Biomaterials have also been utilized in a diagnostic capacity to

improve cancer detection. With continued research into new materials and

their biological interactions, as well as further studies into combining and

optimizing already available strategies, biomaterial technologies represent a

promising potential for future innovations in the treatment of cancer.



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