biomaterials for cancer therapeutics || introduction to biomaterials for cancer therapeutics

© Woodhead Publishing Limited, 2013

3

1 Introduction to biomaterials for cancer

therapeutics

B. K. LEE , Y. H. YUN and K. PARK, Purdue University, USA

and M. STUREK, Indiana University School of Medicine, USA

DOI: 10.1533/9780857096760.1.3

Abstract : Treating cancer requires multiple levels of investigation. Anticancer agents need to be developed through in vitro testing, in vivo animal experiments, followed by clinical studies. Most anticancer drugs are highly hydrophobic and are formulated with excipient materials that increase the water solubility of the drugs, such as co-solvents, liposomes, lipids, polymer micelles, and hydrotropic agents. Anticancer drugs cause serious side effects, so there is a great need to deliver the majority of drug to target cancer cells or solid tumors more specifi cally. This requires development of formulations for targeted delivery. Delivery systems in nanosize, commonly-called nanovehicles, have been frequently used for this purpose. Nanovehicles are also used as an imaging agent for theranosis and as a photothermal agent for thermal ablation of cancer cells. Nanovehicles are engineered to be responsive to environmental changes in temperature or pH for effi cient release of a drug at a target site. While nanovehicles have increased the proportion of the drug delivered to target tumors, the absolute amount of the drug delivered is still very small. New polymeric delivery systems may be necessary to achieve the goal of targeted drug delivery. The testing of the various drugs and delivery systems in vivo is diffi cult, thus it is highly desirable to develop in vitro model systems that can simulate in vivo conditions in humans with the highest fi delity. Proper use of existing biomaterials and development of new biomaterials are necessary to achieve these goals.

Key words: poorly soluble drugs, excipients, nanovehicles, polymers, biomaterials.

1.1 Introduction

1.1.1 Historic approaches to cancer treatment

The history of cancer is extensive. Although the fi rst written document on

cancer may be traced only back to ancient Egypt, around 300 bc (Deeley,

1983), cancer must have existed since the origin of humans. Despite the

50 000 years of modern human history, it was less than 100 years ago when

4 Biomaterials for cancer therapeutics


cancer chemotherapy fi rst began using nitrogen mustard (Gilman, 1963).

While not successful, such an approach led to testing of another drug, meth-

otrexate, opening the door to combination chemotherapy. To alleviate the

often brutal side effects of chemotherapy, so-called targeted treatment was

developed. The targeted treatment here is based on monoclonal antibodies

that interact with specifi c target proteins on the cancer cell surface, or mol-

ecules that interact with receptors existing only on cancer cells. This is the

same as the ‘ magic bullet ’ concept by Paul Ehrlich (Winau et al ., 2004). It is

noted that the targeted treatment is different from ‘ targeted delivery ’ of a

drug to the target cancer cells only (Bae and Park, 2011). Although the goals

of the two approaches, i.e., targeted treatment and targeted drug delivery,

are the same in maximizing the drug effi cacy with minimal side effects, the

two terms need to be distinguished as their approaches are fundamentally

different.

1.1.2 Current and developing approaches to cancer treatment

As of now, it is diffi cult to cure cancer. The most effi cacious therapies are

preventing metastasis through early detection and stopping/slowing of can-

cer cells using cancer drugs, e.g., imatinib (Gleevec ® ) (Klein and Levitzki,

2007). Chemotherapy requires that the side effects of long-term treatment

are manageable. To make the cancer treatment more effective and preven-

tive, improved drug-delivery systems can be developed to make better use

of existing drugs and to promote drugs under development that have dif-

fi cult physicochemical properties. This requires advanced drug-delivery

systems that are usually based on biomaterials with various properties. For

this reason, this chapter briefl y reviews biomaterials that have been used in

cancer treatment.

1.2 Biomaterials used in cancer therapeutics

Cancer therapeutics includes preventive medicine, diagnosis, radiation

therapy, hyperthermia, photodynamic therapy, chemotherapy, and surgical

therapy. Recently, the biomaterials used in delivery of drugs (i.e., therapy)

were also used in delivery of diagnostic agents, and this led to a new dis-

cipline called theranosis (therapy and diagnosis). While there are many

biomaterials suited for targeted drug delivery and theranosis, not many of

them have evolved into testing in human patients. This is largely due to the

reluctance of the pharmaceutical industry to test new excipients that were

not used before in the clinical drug formulations approved by the Food and

Drug Administration (FDA). This is something that the drug-delivery sci-

entists must understand. When a pharmaceutical company develops a new

Introduction to biomaterials for cancer therapeutics 5


anticancer drug, testing its safety and effi cacy is the biggest concern. Adding

an unproven excipient (i.e., any biomaterial that is not a drug) to a poten-

tially blockbuster drug is too risky. If the formulation fails, it is not clear

whether it is due to the drug itself or due to the use of an unproven excipi-

ent. Furthermore, the cost of testing a new excipient in human clinical trials

to show its safety is not trivial. Overall, it has been very diffi cult to introduce

new biomaterials into clinical applications. Those scientists who are aware

of these limitations tend to use so-called ‘generally regard as safe’ (GRAS)

materials that are already proven to be safe for use in humans. While formu-

lation scientists continue their search for novel biomaterials for improving

cancer therapeutics, they need to consider utilizing GRAS materials that

may have better acceptance by the pharmaceutical industry. The number

of GRAS materials that can be used in cancer therapeutics is limited, and

more GRAS materials need to be identifi ed in the future to provide more

fl exibility in designing drug-delivery systems for cancer therapeutics.

In addition to cancer therapeutics, biomaterials are also important in

studying cancers using in vitro models. Before animal and clinical studies

are conducted, in vitro models are used to understand the mechanisms of

drug action and drug-delivery systems. For proper study of drug delivery to

solid tumors, development of three-dimensional (3D) tumor sphere models

is necessary. Many biomaterials have been used in development of in vitro

3D tumor spheroids and tumor spheroid-containing devices.

1.3 Materials used in anticancer formulations

1.3.1 Materials for improving drug solubility

The majority of anticancer drugs currently under clinical use are small mol-

ecules which are often not soluble in water. The poor solubility has been

the main diffi culty in formulating anticancer drugs. Many times the aqueous

solubility of a new drug candidate is so low that it cannot be developed into

a clinically useful drug. Several different approaches have been developed

to increase the water solubility of anticancer drugs. The commonly used

approaches are listed in Table 1.1.

One of the most widely used approaches for increasing the solubility of

poorly soluble drugs is using cosolvent systems. A poorly soluble drug is fi rst

dissolved in an organic solvent, e.g., Cremophor EL for paclitaxel and polysor-

bate for docetaxel (Loos et al ., 2003; Singla et al ., 2002; Sparreboom et al ., 1999). The solution is diluted with aqueous solution before administration by

intravenous (IV) administration. Dilution in water usually results in precipi-

tation of a poorly soluble drug, but the solution can remain stable at least for

several hours for administration without any problem. Liposome formula-

tions have also been used widely in delivering poorly soluble drugs (Modi



et al ., 2012; Mohammed et al ., 2004; Sharma and Sharma, 1997). Liposomal

formulation of doxorubicin has also shown other benefi t of reducing car-

diotoxicity as compared with unencapsulated drug (Abraham et al ., 2005;

Barenholz, 2012; Rahman et al ., 2007). Polymer micelles have been frequently

used for dissolution of poorly soluble drugs in their hydrophobic core. One

of the most widely used polymer micelles is copolymers of poly(ethylene gly-

col) (PEG) and poly(lactic-go-glycolic acid) (PLGA) (Danhier et al ., 2010;

Wang et al ., 2011). Polymer micelles are not stable in blood and may become

disrupted to release the loaded drug (Chen et al ., 2008a, 2008b; Lu et al ., 2011; Miller et al ., 2012). This may not be desirable for delivery of the drug

to a target tumor, but can be acceptable for increasing the drug solubility

for intravenous administration. Polymer micelles can become more stable

by increasing the interaction between a poorly soluble drug and the hydro-

phobic core of polymer micelles using hydrotropic moiety in the hydropho-

bic core (Kim et al ., 2008; Lee et al ., 2007). A hydrotropic agent is useful in

increasing the solubility of a poorly soluble drug by orders of magnitude, but

the use of very high concentrations of the agent limits its clinical applications

Table 1.1 Formulations for improving water solubility of poorly soluble drugs

Method Advantages Disadvantages References

Cosolvent Easy

preparation

Precipitation after

administration,

toxicity

Avdeef et al ., 1999; Loos

et al ., 2003; Simamora

et al ., 2001; Singla et al .,

2002; Sparreboom et al .,

1999

Liposome Long history,

injectable

Very limited

drug loading

capacity,

diffi cult

preparation

Abraham et al ., 2005; Modi

et al ., 2012; Mohammed

et al ., 2004; Rahman

et al ., 2007; Sharma and

Sharma, 1997

Polymer

micelles

Easy

preparation,

injectable

Low stability in

biological fl uids

Danhier et al ., 2010; Lu

et al ., 2011; Miller et al .,

2012; Wang et al ., 2011)

Hydrotropic

polymers

Simple and

easy,

injectable

High concentration

necessary,

toxicity due to

coabsorption

Kim et al ., 2010a, 2008; Lee

et al ., 2007

Lipid

emulsion

Relatively

easy

Diffi culty in lipid

selection

Lukyanov and Torchilin,

2004; M ü llertz et al .,

2010

Nanocrystal No excipient,

good drug

stability

Diffi cult and time-

consuming,

scale-up

problem

Hecq et al ., 2006

Solid

dispersion

No organic

solvent

Low reproducibility,

low drug stability

Sinha et al ., 2010



(Kim et al ., 2010a). This problem can be alleviated by using polymeric

hydrotropic agents. There are hydrotropic agents that increase the drug solu-

bility regardless of the hydrophobicity of the drug, but they are not tested

for their safety, i.e., they do not have GRAS status, making the clinical for-

mulations diffi cult. Lipid emulsion approaches exploit the hydrophobicity of

poorly soluble drugs and a variety of lipids are available for formulation of

poorly soluble drugs (Lukyanov and Torchilin, 2004; M ü llertz et al ., 2010).

The water solubility of poorly soluble drugs can also be increased by

making drug crystals into nanosize (Hecq et al ., 2006). The huge increase

in surface area results in several-fold increase in water solubility. In some

cases, this increase is enough to make a drug effi cacious and clinically viable.

The biggest advantage of using drug nanocrystals is that the drug loading

is close to 100%, even if the surface is modifi ed for improved absorption

to target tumor cells. Solid dispersion approach is based on the formation

of amorphous drug particles by rapidly cooling from the temperature that

melts both drug and polymer (Sinha et al ., 2010; Zhao et al ., 2011). Solid

dispersions are usually for oral administration of poorly soluble drugs, but

they can be applied for intravenous administration if they are prepared in

nanoscale with a controllable size and size distribution.

Cremophor EL and polysorbate were used in the development of clini-

cal products, Taxol ® and Taxotere ® , respectively. Both Cremophor EL and

polysorbate are not safe excipients. Patients must be pretreated with dex-

amethasone to avoid anaphylactic reactions by the excipients themselves.

Paclitaxel and docetaxel simply did not dissolve well in GRAS materials

known at the time of development. Despite the risks associated with using

the materials being real, the benefi t was far greater, justifying the approval

by the FDA. Development of paclitaxel/Cremophor EL and docetaxel/

polysorbate formulations was possible, because big pharmaceutical com-

panies had the incentive and resources to test them in humans. If a new

chemical entity shows unprecedented anticancer effi cacy, but has no suit-

able medium to make a formulation suitable for clinical use, then it is justifi -

able to develop and test new materials in humans even though they have

not been used before. The decision whether a new material will be tested or

not, however, depends on the pharmaceutical companies that must provide

huge resources necessary for clinical studies. This is a dilemma that drug-

delivery scientists are facing. This may be one of the main factors that slow

down the development of new drug-delivery systems.

1.3.2 Formulation for new types of anticancer agents

There are many anticancer drugs that are not small molecules and not

poorly soluble. A new class of anticancer agents includes antibodies, DNA,

siRNA, and vaccines. These molecules are not only hydrophilic, but also



very large. Proteins also need to maintain their tertiary structures to be

functional. This may be a challenge if a sustained release formulation is to

be prepared utilizing excipients such as PLGA, which degrades by hydro-

lysis although it is not water-soluble. It dissolves only in organic solvents,

and making PLGA-based sustained release formulations requires exposure

of proteins to an organic solvent, more precisely to a water‒solvent inter-

face, that can potentially denature the protein and thus its function (Tran

et al ., 2012). Delivery of nucleic acids is different from delivery of proteins,

because of the presence of the high charge density on their surface. Such

ionized macromolecules cannot cross the cell membrane, and thus they are

often condensed by positively charged polymers. The compact complex can

then be endocytosed. The nucleic acid will then have to dissociate itself from

the complex and escape from the endosome to carry out its function (Won

et al ., 2009). Both proteins and nucleic acids need to be delivered in a sus-

tained manner. On the other hand, vaccines may have to be delivered as

a bolus at certain intervals (Aki and Mooney, 2011). This type of pulsatile

delivery may require unique formulations and currently it is not easy to

prepare such systems.

1.3.3 Targeted drug delivery: most ideal, but most diffi cult

Of the many delivery systems for treating cancers, targeted drug-delivery

systems may be the most important, and yet most elusive, formulations.

The idea of targeted delivery has been applied mainly to the delivery of

anticancer drugs to tumors. The concept of the enhanced permeation and

retention (EPR) effect was fi rst described in the 1980s (Matsumura and

Maeda, 1986). Since then, the idea of selectively delivering a drug only to

the target cancer cells has met with numerous nanoparticulate drug-delivery

systems (Goutayer et al ., 2010; Hamaguchi et al ., 2005; Maeda et al ., 2009;

Nichols and Bae, 2012; Singh and Lillard, 2009; Torchilin, 2011; Zhang et al ., 2013). During the last two decades numerous so-called nanotechnology-

based drug-delivery systems have been developed. There is no doubt that

the nanoparticle formulations increase the accumulation of the particles

at the tumor site more than the control, non-nanoparticulate formulations

(Byrne et al ., 2008; Karmali et al ., 2009; Mahon et al ., 2012; Miller et al ., 2013;

Torosean et al ., 2013). It is rather common to see the several-fold increase

in drug delivery to the target tumor sites in the in vivo mouse studies. Such

a large increase has been the focal point of many drug-delivery scientists to

engineer better delivery systems.

While the actual delivery of intravenously administered drug to a tar-

get tumor is highly complex and not clearly understood, the overall process



can be simplifi ed as shown in Fig. 1.1. The intravenously administered

nanovehicles circulate in the blood and extravasate into the surrounding

tissue when they reach a region where a tumor is growing and leaky blood

vessels are common. Since the nanovehicles can accumulate more as they

circulate in the blood longer, extended circulation has been attempted and

the current approach is to graft the nanovehicle surface with PEG, which

is known as PEGylation (Choi et al ., 2009; Pasut and Veronese, 2012; Zhu

et al ., 2010). Nanovehicles can also be used as an embolizing agent, blocking

the blood fl ow to a tumor site. For any nanovehicles to achieve their goal

of killing tumor cells, they must extravasate from blood vessels into the sur-

rounding tissue. Nanovehicles need to be made as small as possible for effi -

cient extravasation. For effi cient extravasation, nanovehicle surfaces can be

engineered to be adhesive to the surface endothelial cells, allowing them to

tumble over the endothelial cell surface until extravasation into a surround-

ing tissue. A mild increase in the local temperature, i.e., mild hyperthermia,

is known to increase the extravasation process (Li et al ., 2013).

Co-solvents

Drug formulations

IV administration

Drug crystals

Nanovehicles

Blood circulationPEGylation

Embolization

Magnetic field,Mild hyperthermia

Diffusion

Nanovehicle–tumorinteraction

Extravasation

Size <200 nm,adhesion to endothelial cells,

mild hyperthermiaTumor

Temperature-sensitivepH-sensitive

Efficient drug release

Photothermal treatment

Endocytosis,escape from endosome

Imaging

Liposomes, polymer micelles, emulsions

1.1 Simplifi ed description of nanovehicle delivery to tumor after

intravenous administration. The administered nanovehicles must go

through multiple steps to reach a target tumor. Effective nanovehicles

need to possess extra functions to release a drug at the right time

and place.



The extravasated nanovehicles must diffuse to a target tumor, and a mild

increase in temperature enhances penetration through the tissue surround-

ing a tumor. Magnetic force may be helpful for enhanced diffusion and nat-

urally magnetic nanovehicles are expected to be useful (Fang et al ., 2012;

Klostergaard and Seeney, 2012), but the magnetic approach has not been

shown to be effective or practical to date. Nanovehicles can be designed

to release a drug at a faster rate near a tumor and this can be achieved by

making the nanovehicles temperature- or pH-sensitive (Felber et al ., 2012;

Kang et al ., 2003; Wang et al ., 2013). If the surface of nanovehicles is modi-

fi ed with a ligand that binds to a receptor on the cancer cell surface, they

are endocytosed more effi ciently (Elias et al ., 2013; Mahon et al ., 2012; Wang

et al ., 2013b). The endocytosed nanovehicles must escape from endosome to

be effective (Won et al ., 2009).

While the nanoparticulate drug-delivery systems have been useful in

targeted delivery that provides signifi cant increase in drug accumulation,

the overall picture of the targeted drug delivery needs to be considered.

It is common to describe the increase in the amount of drug delivered to

a target tumor in terms of percentage increase, e.g., 100–300% increase

(Tinkov et al ., 2010; Zhu et al ., 2010). These are impressive increases, but

they must be understood in the context of the actual amount of the drug

delivered. Usually, the total amount of the drug delivered to a target tumor

by control (e.g., non-particulate) formulation is about 1–2% of the total

dose administered (Hamaguchi et al ., 2005; Wang et al ., 2013b). In this

situation, even if a 300% increase in drug accumulation at a target tumor

is observed by a particulate formulation, it still accounts for only around

5% of the total administered drug (Bae and Park, 2011). The majority of

the administered drug is still distributed to non-tumor sites. This simple

fact is often not considered. Even a small increase in the amount of a

drug delivered to a target tumor can be a viable treatment option, if the

particulate drug-delivery systems are able to cure cancer or allow patients

to live longer with no serious side effects. Unfortunately, however, this has

not been the case.

In most of the in vivo animal experiments, the decrease in the tumor mass

is measured after administration of control and test formulations. The study

is done for a month or so, the decrease in tumor size by the test formulation

becomes apparent, and this is the end point of the study. If the targeted drug

delivery is really effective, the tumor size should decrease close to zero but

this is seldom observed in the literature. If the formulation is administered

beyond 1–2 months of the test period, the animal often dies, because it is

likely that the toxicity of the anti-tumor drug has not been completely elimi-

nated. Thus, caution is necessary when we test the in vivo effi cacy of new tar-

geted drug-delivery systems. We must go beyond the fi rst several weeks of

data and thoroughly characterize toxicity profi les. Furthermore, the animal



species is a signifi cant factor for in vivo toxicology because of the variable

pharmacokinetics in different species. While mice are most commonly used,

large animal models (e.g., dog and pig) should be used because they gener-

ally mimic humans more faithfully and often meet FDA criteria for progress-

ing to human clinical studies (van der Laan et al ., 2010). Reducing toxicity

alone is a signifi cant step toward treating patients. The Doxil ® formulation

(doxorubicin in liposome formulation) is a case in point (James et al ., 1994).

It did not improve the effi cacy of doxorubicin, but it substantially reduced

cardiotoxicity, and this in itself is signifi cant enough to be approved for clini-

cal applications (Barenholz, 2012).

Materials used in nanoparticulate delivery systems

For targeted delivery of an anticancer drug to a target tumor various

nanoparticles have been developed and tested. Initially biodegradable

PLGA nanoparticles loaded with a drug were used (Acharya and Sahoo,

2011; Danhier et al ., 2012; Grama et al ., 2011; Park et al ., 2009). As the

research in nanotechnology intensifi ed during the last decade, a variety of

nanoparticle formulations were developed, ranging from modifi ed natu-

ral polymers, such as glycol chitosan, to gold nanoparticles. The polymer-

based nanoparticles carry drug molecules to the target site so that the

drug concentration at the target is increased (Kono et al ., 2010; Park et al ., 2010; Saad et al ., 2008; Studenovsky et al ., 2012). On the other hand, gold

nanoparticles, solid or hollow, have been used to increase the local tem-

perature around the tumor after the particles accumulate at the tumor

(Agarwal et al ., 2011; Duncan et al ., 2010; Shao et al ., 2013). This hyper-

thermal approach is expected to work well, at least in theory, but it still

faces many hurdles. The same idea of the hyperthermal approach was also

examined using a temperature-sensitive polymer or liposome formulation

designed to increase their contents upon temperature increase (Kost and

Langer, 2012; Oh et al ., 2004; Qiu and Park, 2012).

The nanoparticulate formulations usually have a drug loading level of

20% or less. One apparent improvement to be made is to increase the drug

loading to higher values. This is where delivering drug crystals may provide

substantial advantages (Deng et al ., 2010; Gao et al ., 2012; Muller and Keck,

2004; M ü ller and Keck, 2012; Pohlmann et al ., 2008; Wang et al ., 2012; Zhang

et al ., 2011a, 2011b; Zhao et al ., 2011). The content of a drug in drug crystals

is very high. Even if the drug crystals are covered with a polymer layer for

further surface modifi cation, the drug content will be still very high. The

biodistribution of drug crystals may be signifi cantly different from that of

other nanoparticle formulations. This may reduce the toxicity of a drug in

general. The presumed advantages of nanocrystal approaches, however,

need to be tested and confi rmed from in vivo studies.



1.3.4 Theranosis

Materials that have been used in theranosis include nanovehicles that

contain both an imaging agent and a drug (Accardo et al ., 2013; DeNardo

and DeNardo, 2012; Kim and Jon, 2012; Kim et al ., 2010b; Terreno et al ., 2012; Xie et al ., 2010). Nanovehicles can be polymer micelles, nanogels, nan-

oliposomes, and nanocrystals. Currently, these nanovehicles are mainly used

in animal studies, but they have a great potential in clinical use. The pres-

ence of an imaging agent allows identifi cation and quantitation of a delivery

system at a target site. Furthermore, the theranosis system can be used to

identify the boundary between a solid tumor and the surrounding normal

tissue. Clear identifi cation of such a boundary is critical in surgical removal

of tumor without damaging normal tissue.

1.3.5 Materials for in vitro models

The most common approach to developing new drug-delivery systems is

to test in vitro fi rst and, if a system shows a promise, then an in vivo ani-

mal study is conducted. Since doing an animal study requires much more

resources than an in vitro study, it is always desirable to develop in vitro

models that can represent or predict the results of animal studies. While

there is a concern that in vitro models do not accurately represent an in vivo

environment, good in vitro models are necessary, especially when a large

number of systems need to be screened.

Drug candidates are usually tested for their anticancer activity using either

a cell suspension or a two-dimensional (2D) cell culture system. Since solid

tumors are three-dimensional (3D) structures that prevent free diffusion

of a drug and/or a nanovehicle into the core of the tumor, the drug effi cacy

observed in 2D systems may not represent the actual effi cacy in a solid tumor

(Godugu et al ., 2013; Kim, 2005; Lan and Starly, 2011; Talukdar and Kundu,

2012; Xu et al ., 2012; Yoshii et al ., 2011). For this reason, we need to develop

in vitro 3D models of tumor spheroids. Currently, Matrigel is widely used

to grow cancer cells in 3D spheroids (Fischbach et al ., 2007; Kleinman and

Martin, 2005; Sodunke et al ., 2007), but other biomaterials with well-defi ned

preparation and reproducible properties need to be developed. The concept

of an in vitro tumor spheroid model can be further developed into the so-

called tumor-on-chip or organ-on-chip systems (Kim et al ., 2012; Shin et al ., 2013; Torisawa et al ., 2005; Wlodkowic and Cooper, 2010; Wu et al ., 2011;

Zi ó lkowska et al ., 2013). Such in vitro systems are urgently needed to test

numerous drug and drug-delivery systems. For tumor-on-chip approaches,

polymeric microscopic fl uid systems need to be developed to mimic natural

blood vessels using polymers that have desirable properties, such as porosity

to control the diffusion of proteins and the ability to support cell growth.



1.4 Conclusion and future trends

Successful treatment of cancers requires development of effective drugs

and proper delivery systems that can deliver drugs selectively to target cells.

To make signifi cant progress in cancer chemotherapy, studies must be more

critical. The data obtained from in vivo animal studies need to be inter-

preted more carefully and comparison of multiple species is ideal to better

model human clinical conditions. Some formulations may show signifi cant

increase in the drug accumulated at the target site, but the effi cacy needs to

be examined in terms of its ability to shrink tumor size long term without

toxic side effects. The data observed in a single animal species (e.g., mouse)

cannot be generalized or extrapolated to humans with confi dence.

To translate the technology obtained from in vitro and in vivo animal

studies to clinical application, the current approaches need to be re-

examined, in particular using biomaterials to make nanoparticles. Better

in vitro model systems must be developed to mimic in vivo conditions

more accurately, and more importantly, more relevant to humans. In addi-

tion, better delivery systems need to be developed. Simply using a nano-

sized delivery system is not enough to achieve true targeted drug delivery.

The information currently available from the decade-long research on

nanovehicles is a good starting point to design novel biomaterials ideally

suited for treating cancers.

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