Polymeric drug delivery systems for localized cancer chemotherapy

Abstract

Cancer has become one of the most difficult health challenges of our time, accounting for millions of deaths yearly. Systemic chemotherapy is the most common therapeutic approach; however, considerable limitations exist including toxicities to healthy tissues and low achievable drug concentrations at tumor sites. More than 85% of human cancers are solid tumors, which can greatly benefit from localized delivery. This approach allows for high drug concentrations at the target site, lower systemic toxicity, and extended drug exposure which may be beneficial for cell cycle-specific drugs. Polymers have been widely considered in the development of localized delivery systems. This review focuses on both natural and synthetic biodegradable polymers that have been explored for localized chemotherapy, exploring their advantages, disadvantages, and clinical potential while citing examples of their use in pre-clinical development.

Keywords::

• Biodegradable and biocompatible
• localized delivery systems
• natural polymers
• synthetic polymers
• cancer

Introduction

Cancer is one of the leading causes of death worldwide, accounting for millions of deaths each year (Ma & Yu, 2006). Systemic chemotherapy is the most commonly used therapeutic strategy, although considerable limitations exist. It involves intravenous administration of anti-cancer drugs at maximum tolerable doses, which leads to severe toxicities in healthy tissues that range from neutropenia to cardiomyopathy (Gasparini, 2001; Scharovsky et al., 2009). Further, systemic chemotherapy is not efficient in delivering drugs to target sites at therapeutic concentrations, and maintaining adequate drug levels within tumors is a challenge (Jang et al., 2003). Chemotherapeutic delivery to solid tumors systemically involves barriers, including transport along the blood circulatory system to tissues, across vasculature walls into distant tumor sites and through interstitial space within a tumor (Jang et al., 2003). As a result, only a fraction of the administered dose reaches tumor cells, limiting therapeutic efficacy and increasing toxicity to healthy tissues.

Although various routes for chemotherapeutic delivery have been investigated (Table 1), localized delivery has gained increased attention in cancer therapy. This strategy maintains low systemic drug levels while ensuring therapeutic levels at tumor sites. As solid tumors account for 85% of all cancers, this strategy has the potential to dramatically deliver more efficient drug therapy (Figure 1) (Fung & Saltzman, 1997; Jang et al., 2003). In this review, localized chemotherapy refers to implantation or injection within (i.e. intra-tumoral) or in close proximity to the tumor site(s). Drug retention at target sites, which decreases systemic drug exposure, is an important consideration for minimal toxicity and maximal efficacy. This can be accomplished through the use of biomaterials which can retain the drug at the desired implant sites.

Table 1.  Different approaches of administration for cancer chemotherapy (adapted from Exner & Saidel, 2008).

Type	Route	Drug delivery platforms	Clinically used or tested systems
Systemic	Intravenous	Micelles, liposomes, nanoparticles	Doxil^®, DaunoXome^®, Abraxane^®, iMyocet^®
	Subcutaneous /intramuscular	Micro- or nanoparticles, polymer implants or injectables	Eligard^®, Zoladex^®, DepoCyt^®, Lupron Depot^®, Sandostatin LAR^®, Suprefact^® Depot, Trelstar™ Depot
	Oral	Sustained-release tablets, capsules, others	Gleevec^®, Tarceva^®, Xeloda^®, Iressa^®
Local	Intra-peritoneal	Micro- or nanoparticles	Paclimer^® (failed clinical trials due to biocompatibility issues)
	Intra-tumoral	Polymer implants or injectables	Gliadel^®, OncoGel™

Figure 1.  Advantages of localized chemotherapy over conventional systemic chemotherapy for the treatment of solid tumors.

Polymers have been widely explored in the area of drug delivery due to their customizable nature which allows for the development of various systems such as implants, pastes, hydrogels, and/or micro/nanoparticles (Jagur-Grodzinski, 2009; Kim et al., 2009). The options for fabricating polymeric drug delivery systems are vast; however, one of the challenges in their use is biocompatibility (Park & Park, 1996). The immune response elicited by a polymeric material can result in adverse effects as well as influence drug release properties (Rihova, 1996). An acute inflammatory response occurs upon implantation or injection and activation of macrophages, foreign body giant cells, and fibroblasts, resulting in fibrous encapsulation of the system (Rihova, 1996; Park & Park, 1996). This encapsulation is a normal tissue response to a foreign material and does not necessarily denote a lack of biocompatibility, such as calcification and necrosis would (Rihova, 1996). However, the extent of encapsulation and its effects on drug release will dictate the biocompatibility of the material. It is also important to consider the degradation products of a polymer, as these may elicit immune or toxic responses. Biodegradation is also important, since surgical removal of the delivery system would decrease patient compliance. Factors influencing biodegradation of polymers include chemical structure and composition, physico-chemical factors (ion exchange, ionic strength, and pH), physical factors (shape, size, and porosity), morphology or microstructure, and whether degradation occurs through enzymatic or hydrolysis routes (Pillai & Panchagnula, 2001). These properties must be carefully considered when designing drug delivery systems so that proper biodegradation can be ensured.

Table 2 outlines biodegradable polymers investigated for drug delivery applications. Although localized chemotherapy is promising, only a few polymer-based formulations have reached clinical testing. These include the poly(lactic-co-glycolic acid) (PLGA) based localized injectable delivery system OncoGel™ (Elstad & Fowers, 2009) and the implantable system Gliadel^® Wafer, composed of a polyanhydride copolymer, for treatment of brain cancer (Westphal et al., 2003; Attenello et al., 2008). Many polymeric delivery systems for localized chemotherapy fail to reach the market as results obtained pre-clinically often do not translate successfully in clinical development. An example is Paclimer^®, polyphosphoester microspheres for localized delivery of paclitaxel. This formulation showed promise in pre-clinical studies but failed during Phase I testing due to biocompatibility issues associated with the polymer (Harper et al., 1999; Armstrong et al., 2006).

Table 2.  Biodegradable polymers used in drug delivery applications (adapted from Pillai & Panchagnula, 2001).

Polymer	Classification	Examples
Natural	Polysaccharides	Chitosan, dextran, cyclodextrin, agarose, alginate, hyaluronan (hyaluronic acid)
	Protein-based	Collagen, albumin, gelatin
Synthetic	Polyesters	Poly(lactic acid), poly(glycolic acid), poly(hydroxy butyrate), poly(ϵ-caprolactone), poly(dioxanones)
	Polyanhydrides	Poly(sebacic acid), poly(adipic acid), poly(terphthalic acid)
	Phosphorous-based	Polyphosphates, polyphosphonates, polyphosphazenes
	Others	Poly(cyano acrylates), polyurethanes, polyortho esters, polydihydropyrans, polyacetals

This review will explore biodegradable polymeric drug delivery systems pre-clinically investigated for localized chemotherapy that have shown anti-tumor promise in animal models of cancer. We have chosen to focus on delivery systems for chemotherapeutics only; thus, systems designed to deliver biologics will not be discussed. This review discusses polymers employed as carriers, and therefore does not include polymer–drug conjugates. Specifically, the review outlines both naturally occurring and synthetic polymers including polysaccharides (chitosan, alginates, and hyaluronan), protein-based polymers (collagen, gelatine, and albumin), polyesters, and polyanhydrides. Advantages, disadvantages, and clinical potential of the different classes of polymers are discussed.

Natural polymers

Natural polymers are extracted from abundant natural resources and many have excellent biocompatibility and degrade into non-toxic, non-immunogenic components (Pillai & Panchagnula, 2001). These include polysaccharides and protein-based polymers. Polysaccharides interact with living cells and have excellent hemocompatibility, while protein-based polymers form scaffolds that resemble the extracellular matrix and are, therefore, retained within the site of administration (Malafaya et al., 2007). As described below, localized chemotherapeutic delivery systems formed from natural polymers show great promise. However, certain drawbacks exist including complexities associated with their purification, immunogenicity, difficulties in processing, the possibilities of disease transmission from their source organisms to humans, and batch-to-batch variations (Lee & Shin, 2007; Nair & Laurencin, 2007).

Polysaccharides

Polysaccharides are biopolymers that consist of simple sugar units. Variations in the nature, molecular weight, and structure of these units give rise to the variety of polysaccharide-based polymers available (Chourasia & Jain, 2004). These are generally inexpensive as they are abundantly found in nature and can be derived from algals (e.g. alginate), plants (e.g. pectin, guar gum), microbes (e.g. dextran, xanthan gum), and animals (e.g. chitin, chondroitin) (Sinha & Kumria, 2001). They are stable, non-toxic, and are good candidates for developing biocompatible drug delivery materials (Liu et al., 2008). The hydrophilic groups that are found on polysaccharides such as chitosan, alginates, and hyaluronan form bioadhesions with biological tissues, potentially increasing drug retention in tissues such as cancerous tumors (Liu et al., 2008).

Chitosan

Chitosan is a linear natural polysaccharide composed of β-(1→4)-2-amido-2-deoxy-D-glucan (glucosamine) and β-(1→4)-2-acetamido-2-deoxy-D-glucan (acetyl glucosamine) units, and is obtained by deacetylation of chitin, which is found in crustaceans, insects, and certain fungi (Mourya & Inamdar, 2008). Chitosan has excellent biocompatibility, low toxicity, immunostimulatory activities, antibacterial and anti-fungal action, and anti-coagulant properties (Dodane & Vilivalam, 1998; Kumar, 2000). Furthermore, the degradation products of chitosan (i.e. aminosugars) are non-toxic, non-immunogenic, and non-carcinogenic (Muzzarelli, 1993; Zheng et al., 2007). In cancer therapy applications, chitosan is attractive as it has demonstrated anti-tumor activity (Qin et al., 2002; Maeda & Kimura, 2004). Unfortunately, chitosan-based localized delivery systems have not yet reached clinical use. Achieving a high degree of purity is a great challenge, and contaminants or unreacted cross-linking agents can significantly impact chitosan’s safety profile (Kean & Thanou, 2010). Furthermore, some chitosan derivatives are not degraded by natural enzymes ). Once these and other issues have been resolved, chitosan will likely have wide clinical application, as it has shown much promise in pre-clinical studies.

Ta et al. (2009) recently formulated an injectable chitosan-based doxorubicin hydrogel for osteosarcoma therapy. The hydrogel released its drug load over 19 days, effectively inhibiting primary tumor growth and metastasis to an extent 1.5-fold greater than free doxorubicin, while also decreasing the systemic toxicities associated with this drug. Chitosan was also employed by Ruel-Gariepy et al. (2004) to prepare an injectable paclitaxel delivery system that uses the BST-Gel™ platform technology developed at Biosyntech Inc., intended for intra-tumoral injection in the treatment of breast cancer. The group formulated an in situ thermosensitive gelling hydrogel that is liquid at room temperature and becomes a gel implant upon injection. One intra-tumoral injection (40 mg/kg) resulted in equivalent tumor inhibition to that obtained after four 10 mg/kg doses of intravenous paclitaxel in a murine xenograft model of breast cancer. Another thermosensitive chitosan hydrogel system has been recently developed by Han et al. (2008) for the simultaneous intra-tumoral delivery of doxorubicin and the vaccinia virus to elicit immune-mediated destruction of tumors. While immunotherapies are not effective against established tumors on their own, synergistic effects are seen when combined with cytotoxic agents. When compared to monotherapy, greater anti-tumor activity and prolonged survival were observed in a subcutaneous murine model of cervical cancer.

Grant et al. (2005) designed an implantable chitosan film formulated with phospholipids to provide continuous intra-peritoneal delivery of paclitaxel in the treatment of ovarian cancer. No fibrous encapsulation or toxicities of drug-free or paclitaxel-loaded film were observed in mice over a 4-week period after implantation in the peritoneal cavity (Ho et al., 2005). Complete tumor inhibition was achieved in a murine xenograft model of human ovarian cancer, whereas only 47% inhibition was observed in animals given equivalent bolus intraperitoneal doses of paclitaxel (Vassileva et al., 2007). Intermittent doses of paclitaxel also caused a pronounced induction of MDR1/P-glycoprotein, which plays a large role in multi-drug resistance, while continuous delivery of paclitaxel provided by the film did not cause MDR1 induction (Ho et al., 2006). To circumvent the need for surgical implantation, Grant et al. (2008) and Zahedi et al. (2009) more recently developed injectable chitosan-phospholipid depot forming formulations for paclitaxel and docetaxel, respectively. No signs of toxicity or inflammation were detected upon administration of drug-free or drug-loaded formulation, and only a very thin fibrous capsid was observed within 1 month which did not interfere with in vivo drug release (De Souza et al., 2009; Zahedi et al., 2009). A dose-dependent response of the docetaxel formulation was observed in a xenograft model of human ovarian cancer in mice, with significant tumor inhibition of 87.3 ± 9.3% at clinically relevant doses (Figure 2) (Zahedi et al., 2009).

Figure 2.  An injectable polymer-lipid docetaxel formulation (PoLi_gel-Docetaxel) is efficacious in the localized treatment of SKOV3 ovarian cancer xenografts. The PoLi_gel-Docetaxel was injected intraperitoneally 14 days following SKOV3 inoculation. Significant difference was found between treatment groups and controls (p < 0.05). Error bars are expressed as standard error (n = 4). Adapted from Zahedi et al. (2009).

Obara et al. (2005) created an in situ forming chitosan-based hydrogel system for subcutaneous intra-tumoral drug delivery. An azide-chitosan-lactose derivative (Az–CH–LA) solution containing paclitaxel was injected beneath subcutaneous tumors derived from Lewis lung cancer cells. An optical fibre was then inserted into the Az–CH–LA solution through the needle pore and UV-laser irradiation was performed for 30 s to convert the solution into an insoluble hydrogel matrix. Over a 14 day study period, the paclitaxel-incorporated Az–CH–LA hydrogel inhibited tumor growth more effectively than drug-free Az–CH–LA hydrogel or free paclitaxel. Furthermore, there was a marked reduction in the number of CD34-positive vessels in the tumor microenvironment, indicating a strong inhibition of angiogenesis.

The effectiveness of using a chitosan-β-glycerophosphate (C-GP) system to locally deliver sustained doses of camptothecin to a RIF-1 fibrosarcoma mouse model was demonstrated in a study by Berrada et al. (2005). Intra-tumoral injection led to greater tumor reduction than intra-peritoneal doses of camptothecin. Animals treated in this manner reached the end points on day 8, while those treated with C-GP-loaded camptothecin survived for 25 days.

Alginates

Alginate is a natural linear anionic heteropolysaccharide consisting of repeat units of β-D-mannuronic acid (M) and its C-5 epimer, α-L-guluronic acid (G) joined together by 1,4-glycosidic linkages (Shilpa et al., 2003). Alginates are extracted from brown seaweed and are recognized for their lack of toxicity as evidenced in pre-clinical studies (Tonnesen & Karlsen, 2002). This polymer has great potential for applications in drug delivery, owing to its incredible versatility. For instance, both neutral and charged gels can be made depending on the pH of the preparation medium, allowing for retention of drugs with a wide range of physicochemical properties. Yet, as with other polymers extracted from natural sources, many impurities are co-extracted with alginates including endotoxins, heavy metals, and proteins (Tonnesen & Karlsen, 2002). Pyrogenicity can be controlled, but not completely eliminated, if ultrapure grades of alginates are used. Thus, local delivery systems formed from alginates are still in the pre-clinical development stage.

Recently, Abe et al. (2008) investigated a local delivery system for paclitaxel in the form of hydroxyapatite-alginate composite beads for therapy of metastatic spine cancer in a rat model. Animals in the control group (drug-free beads) developed hind-limb paralysis at 11 days and died within 16 days. Animals treated with intra-tumoral injections of the paclitaxel-loaded beads showed a 140–150% prolongation in disease-free survival compared to controls. Moreover, significant therapeutic effects were not seen in animals dosed with up to 30-fold higher intravenous doses of paclitaxel solution, highlighting the enhanced effect of localized delivery. Bouhadir et al. (2001) developed a hydrogel for localized and controlled delivery of anti-cancer agents by oxidizing sodium alginate and cross-linking with adipic dihydrazine. The amount of adipic dihydrazine used in the formulation was modified to manipulate the rate of drug release, which could be varied from days to weeks due to ionic interactions between the drugs and the polymer. The formulations can successfully load and release methotrexate, doxorubicin, and mitoxantrone simultaneously or individually. An alginate implant to encapsulate endostatin-secreting cells for the treatment of malignant brain tumors was also developed by Read et al. (2001). Sustained local release of endostatin from the implant was found to successfully decrease vascular density and diameter, inhibiting glioma cell invasion, and decreasing tumor volume. The anti-angiogenic activity of endostatin was tumor-specific, as vessels from healthy tissues formed over the implant. The authors examined the biocompatibility of the system subcutaneously and intracranially, both of which showed no signs of an immune reaction.

Hyaluronan

Hyaluronan (also referred to as hyaluronic acid) is an anionic, non-sulfated glycosaminoglycan composed of D-glucuronic acid and D-N-acetylglucosamine, linked via alternating β-1,4 and β-1,3 glycosidic bonds, and is distributed widely throughout connective, epithelial, and neural tissues (Fraser et al., 1997). Hyaluronan and its derivatives have been developed as topical, injectable, and implantable vehicles for the delivery of biologically active molecules due to their biocompatibility, unique viscoelastic nature, and non-immunogenicity (Liao et al., 2005; Yadav et al., 2008). However, their use in the development of localized delivery systems of anti-cancer agents has been rather limited. Recently, Al-Ghananeem et al. (2009) reported on novel paclitaxel-loaded cross-linked hyaluronan nanoparticles for the local treatment of breast cancer. Intra-tumoral administration of the drug-loaded nanoparticles in female rats showed effective inhibition of tumor growth in all treated rats over 50 days. In the case of the free paclitaxel-treated group, the mean tumor volume increased linearly to a size that was 4.9-fold larger than the baseline volume at 57 days post-drug administration.

Protein-based

Proteins are amino acid polymers arranged in a three-dimensional folded structure. As one of the most important classes of biomolecules, proteins play a vital role in virtually every intra- and extra-cellular process. Proteins and other amino acid-derived polymers are major components of natural tissues, as such they are the preferred biomaterials for development of sutures, hemostatic agents, and scaffolds for tissue engineering (Nair & Laurencin, 2007). Furthermore, protein-based biomaterials are known to undergo naturally-controlled degradation. They generally show good biocompatibility, due in part to their ability to mimic the extracellular matrix (Malafaya et al., 2007). A significant advantage of protein-based polymers over polysaccharides is the ability to use recombinant protein technologies which allows polymer properties to be precisely defined, which decreases batch-to-batch variation (Malafaya et al., 2007). On the other hand, as proteins are very susceptible to degradation, a major limitation in the clinical use of these polymers is the development of stable formulations (Hawe & Friess, 2007). The principal protein-based polymers that have been used to develop localized chemotherapy formulations include albumin, collagen, and gelatin.

Albumin

Albumin is a protein of 584 amino acids, is highly soluble, has a strong negative charge, and makes up half of the normal intra-vascular protein mass (Mendez et al., 2005). Albumin has been used in microsphere preparation for lipophilic drug delivery due to its widespread availability in nature, lack of toxicity and anti-genicity, and its ability to prolong drug levels in the systemic circulation (Patil, 2003). One obstacle in making albumin available for clinical use is that albumin is extracted from human or animal plasma, posing the risk of blood-borne pathogen transmission (Hawe & Friess, 2007). This can be avoided by high-temperature pasteurization, which could in turn denature the protein. However, various desirable properties of albumin make it an attractive natural polymer for localized delivery of anti-cancer agents. For instance, albumin has been observed to accumulate in the tumor interstitium, resulting in high intra-tumoral concentrations of drugs bound to it (Rugo, 2008).

A novel tissue adhesive composed of human serum albumin (HAS) and tartaric acid derivative (TDA) was developed for delivery of doxorubicin hydrochloride (Kakinoki & Taguchi, 2007). Intra-tumoral injection in mice with subcutaneous human colon carcinoma xenografts reduced tumor volume compared to non-treated, doxorubicin hydrochloride, and drug-free HSA–TAD system treatment groups. Another formulation exploring intra-tumoral delivery was developed by Almond et al. (2003), in the form of injectable mitoxantrone-albumin microspheres for breast cancer treatment. When administered intra-tumorally in a murine mammary adenocarcinoma model, greater survival was observed, and much larger doses could be tolerated than that seen after systemic administration. Intra-tumoral delivery is particularly beneficial in breast cancer, as drug that escapes the tumor microenvironment will drain through the lymph nodes, which is the most common site of breast cancer metastasis (Almond et al., 2003).

Collagen

Collagen is the main structural protein in the bodies of all vertebrates (Gelse et al., 2003). Due to its large abundance in the human body and high biocompatibility, collagen has been used for several years in suturing materials and has current widespread application in tissue engineering (Wallace & Rosenblatt, 2003). In localized chemotherapeutic applications, collagen has been under-explored, one issue being that collagen has poor mechanical properties, undergoing rapid degeneration shortly after implantation (Friess, 1998). One approach to overcome this is through cross-linking methods.

Recently, Ye et al. (2008) developed a collagen film loaded with polylactic acid microspheres containing epirubicin for intra-tumoral implantation. Intra-tumoral implantation in a murine liver cancer model resulted in considerably greater tumor inhibition than intra-tumoral administration of the epirubicin microspheres alone. Prior to this study, the only other application of collagen for localized chemotherapeutic delivery found in the literature dates back to 1995, when Davidson et al. (1995) evaluated a collagen matrix for localized delivery of cisplatin following tumor resection, which completely prevented tumor recurrence in all experimental animals, whereas administration of cisplatin solution led to bulky tumor recurrence. The viscous collagen matrix was able to contain the drug at high levels in the resection site for 7 days, leading to prolonged local exposure while sparing healthy tissues.

Gelatin

Gelatin is a natural, biocompatible, and non-toxic macromolecule obtained by denaturing of collagen derived from the skin, white connective tissue, and bones of animals (Nezhadi et al., 2009). Concerns exist over transmittance of pathogens such as prions that survive the high temperatures required for the denaturation process. As such, synthetic or plant-derived collagen is often favorable in biomedical applications (Olsen et al., 2003).

Konishi et al. (2003) have studied a gelatin hydrogel for localized cisplatin delivery, which was evaluated in a subcutaneous model of fibrosarcoma in mice. The hydrogel was injected directly under the tumor mass. The localized release of cisplatin over 14 days resulted in a significant anti-tumor effect and improved survival, while eliminating the undesirable side-effects associated with systemic cisplatin administration. Hanes et al. (2001) developed injectable gelatin-based microspheres for the long-term localized delivery of bioactive interleukin-2 (IL-2) for anti-tumor immunotherapy. More specifically, IL-2 was encapsulated into gelatin and chondroitin-6-sulfate using an aqueous-based complex coacervation technique. Anti-tumor efficacy of this system was studied in primary (9L gliosarcoma) and metastatic (B16-F10 melanoma) brain tumor models in rats and mice, respectively, as well as a murine liver tumor model (CT26 carcinoma). Release of IL-2 from the gelatin microspheres occurred over 2 weeks in vitro and significant levels were seen for up to 21 days in vivo. The gelatin IL-2 microspheres injected intra-tumorally were more effective in protecting animals challenged with fatal tumor doses in the brain and the liver than placebo or autologous tumor cells genetically engineered to secrete IL-2. Localized delivery of a gelatine-based doxorubicin formulation was also achieved by Stuart et al. (1993) using a chemoembolization technique. This formulation was injected in hepatic arteries closest to the tumors, which were catheterized so that the formulation would remain localized. The 69% overall response rate as a result of treatment was significant, although changes in disease-free survival times were not achieved.

Synthetic polymers

As synthetic polymers can be tailor-made or modified to provide desirable mechanical and chemical properties for specific applications, they are commonly used in the development of novel drug delivery systems (Ghosh, 2004). Importantly, unlike natural polymers, synthetic polymers pose very little risk of immunogenicity and disease transmission. On the other hand, due to their synthetic nature, these polymers often lead to inflammatory reactions, low clearance rates, and localized drops in pH due to acidic degradation products (Lee & Shin, 2007). However, formulations based on synthetic polymers for localized chemotherapy have reached clinical use as discussed below, which demonstrates that the benefits associated with these polymers outweigh their disadvantages.

Polyesters

Polyester-based polymers are the most widely explored class of biodegradable polymers for drug delivery applications, with poly(lactic acid-co-glycolic acid) (PLGA) alone being associated with more than 500 patents (Anderson & Shive, 1997; Pillai & Panchagnula, 2001). The majority of approved pharmaceutical implants that are commercially available are based on PLGA. While these polymers have been criticized for acidic degradation products that can cause local irritation and instability of the drugs being delivered (Taylor et al., 1994; Athanasiou et al., 1996; Fu et al., 2000), polyester-based polymers such as PLGA are considered biocompatible and biodegradable, and are therefore attractive candidates for use in drug delivery systems.

PLGA has been used to develop a wide range of localized delivery systems, including microparticles, pastes, and implants. As many drugs and their vehicles are not able to penetrate the blood–brain barrier, Lee et al. (2005) developed a wafer formulation for the treatment of gliosarcoma. The wafer was prepared by compressing mixtures of PLGA and 1,3-bis(2-chloroethyl)-1-nitrosourea (carmustine, also known as BCNU), which released over a period of 7 days. Implantation adjacent to the tumor site was efficacious in a subcutaneous xenograft model of gliosarcoma. Since development of BCNU resistance in the brain is a concern, a paclitaxel-loaded thin PLGA implant was developed by Ranganath and Wang (2008). The authors claim that this thin implant provides a greater surface area-to-volume ratio than wafers, resulting in a more favorable drug release profile. Indeed, results show a low initial burst release of paclitaxel followed by a constant and prolonged release for over 80 days. A 30-day study in a subcutaneous tumor model showed greater tumor inhibition in animals treated with the paclitaxel-loaded implant than in animals treated intra-tumorally with the commercially available formulation of paclitaxel (Taxol^®).

Azouz et al. (2008) have investigated a PLGA microsphere formulation for paclitaxel delivery. In this study, PLGA microspheres loaded with paclitaxel were found to successfully inhibit local tumor growth after local injection following lung tumor resection. A large advantage of microspheres over implants is injectability, however there is a disadvantage in that there is a great potential for rapid migration to other tissues and into the systemic circulation. A solution to this is the development of injectable systems which can form a gel in situ. D’Souza et al. (2006) developed an injectable PLGA gel capable of releasing bleomycin over 30 days, which significantly inhibited tumor growth in a murine intra-dermal model of fibrosarcoma.

An injectable PLGA drug delivery implant for use in the treatment of head and neck cancers has been studied by Desai et al. (2008). PLGA millicylinders were used to formulate N-acetylcysteine, a drug that inhibits extracellular matrix degradation, thereby not allowing tumor progression. The millicylinders were prepared by slowly extruding a solution of drug and polymer through a syringe and into silicone tubing, which was dried and cut to extract solid millicylinders. Continuous drug release was achieved for over 1 month, although efficacy has not yet been tested in vivo. Weinberg et al. (2007) formulated doxorubicin-loaded PLGA millirods for the treatment of liver cancer. PLGA microspheres were mixed with doxorubicin/NaCl powder using a mortar and pestle, and the mixture was packed and compressed to form millirods. Intra-tumoral treatment proved to be efficacious in a liver cancer model in rabbits. Necrosis could be detected in the tumors from the site of implantation, indicating that the prolonged 8-day release of doxorubicin caused damage to tumors while sparing the healthy liver tissue surrounding them.

Polyanhydrides

Like polyesters, polyanhydrides are a class of synthetic polymers widely studied for drug delivery applications. A significant advantage of polyanhydrides over polyesters is that they degrade into metabolites that are not cytotoxic or inflammatory (Kumar et al., 2002). These highly biocompatible polymers can be manipulated to yield drug release from days to months (Jain et al., 2005). The most successful application of polyanhydrides in localized cancer therapy is the FDA-approved polyanhydride poly(1,3-bis-(p-carboxyphenoxy propane)-co-(sebacic anhydride), or P(CPP-SA), for drug delivery in brain cancer (Wang et al., 2002). The commercially available formulation Gliadel^® employs P(CPP-SA) in the form of a dime-sized wafer that is implanted at the site of tumor resection and gradually releases BCNU (Jain et al., 2005). This system is advantageous over the BCNU-PLGA wafer, as PLGA is known to elicit inflammatory reactions (Hickey et al., 2002; Fulzele et al., 2003; Grayson et al., 2004). Clinical trials have shown that when the wafer is inserted at the tumor resection site, it provides continuous drug release for 7–10 days post-implantation, and survival is prolonged in patients with recurrent malignant glioma (Jain et al., 2008).

Many localized delivery systems that have been evaluated pre-clinically have been formed from P(CPP-SA). For example, Berrada et al. (2002) used this polymer to deliver 5-fluorouracil intra-tumorally. The polymer was mixed with drug, ground into a fine powder, heated, and extruded to form rods, which were implanted via a trocar into fibrosarcoma tumors established subcutaneously in mice. Although the entire drug load was released within 3 days, with half released within 24 h, tumor growth inhibition resulting from intra-tumoral implantation was significantly greater than that resulting from systemic administration of 5-fluorouracil alone. P(CPP-SA) was also used by Storm et al. (2002) to develop a localized delivery system for camptothecin, a very potent anti-cancer agent that has limited use due to high systemic toxicity. Drug-containing polymer discs were implanted in the brains of rats inoculated with gliosarcoma cells. Discs loaded with camptothecin resulted in an impressive median survival of 69 days, while control non-treated animals had a median survival of 17 days. The authors detected no systemic toxicity as a result of the treatment. Shikani and Domb (2000) evaluated the in vitro and in vivo efficacy of four anti-cancer agents (cisplatin, fluorouracil, methotrexate, and paclitaxel) loaded into implantable disks formed from a copolymer of fatty acid dimmer (FAD) and sebacic acid (SA), poly(FAD:SA), for localized delivery in the treatment of head and neck cancer. Efficacy of the cisplatin-poly(FAD:SA) disc was evaluated in a murine xenograft model of human mouth carcinoma, in which the polymer disc was implanted adjacent to the subcutaneous tumor. Tumor growth delay was doubled compared to animals receiving intravenous doses of cisplatin. In addition, the localized delivery strategy resulted in a reduction in systemic toxicity, with LD₅₀ values 4-times greater than systemic administration. Polyanhydride polymers were used by Hsu et al. (2005) to explore the concept of multimodal therapy. The polymers were loaded with the anti-angiogenic drug adriamycin and were compressed to form disc-shaped implants. The discs were implanted intra-cranially in a gliosarcoma tumor model in rats after intra-cranial administration of gelatin microspheres loaded with interleukin-2 (IL-2). The administration of IL-2 leads to a strong immune reaction that eventually leads to necrosis of tumor cells. This action, coupled with the inhibition of angiogenesis, led to a median survival of 53 days, which is significantly greater than the median survival times of 30 and 39 days seen in rats treated with adriamycin-loaded polyanhydride polymer or IL-2 gelatin microspheres monotherapy, respectively. A very similar approach was adopted by Rhines et al. (2002), whereby IL-2-loaded gelatin microspheres were injected intra-cranially in a gliosarcoma model in rats, and polyanhydride polymer wafers were used to deliver BCNU. As was done by Hsu et al. (2005), the wafers were implanted 5 days after administration of the microspheres. The synergetic effect of immunotherapy and chemotherapy was evident, as median survival of animals treated with combination therapy was ∼ 2-fold greater than monotherapy with either agent.

Challenges and concluding remarks

As a dominant killer in the developing world, cancer is one of the most difficult health challenges of our time. Various treatment strategies have been explored to improve upon current systemic chemotherapy methods. Localized delivery of chemotherapeutics for solid tumors is one approach that has been considered in recent years. Biodegradable polymeric systems, both natural and synthetic, in the forms of microparticles, implantable wafers and films, injectable pastes, and gels have been investigated for this purpose due to their customizability. These formulations must be further pursued into clinical development, as they have shown great promise pre-clinically. Synthetic polymers have reached clinical use for localized delivery in cancer therapy. The success of these polymers is attributed to the high level of control in their production and customization, and minimal risk of disease transmission, an issue that poses great concern in the use of natural polymers. As illustrated by the various examples cited in this review, natural polymers show incredible potential as localized chemotherapeutic delivery systems due to their superior biocompatibility, biodegradability, and lack of immunogenicity, properties that are attributable to the presence of these polymers in living organisms, including the human body. Unfortunately, the fact that these polymers come from natural sources poses many challenges that have hindered their clinical use in this application, including concerns over pathogen transmission, purity, stability following sterilization, batch-to-batch variations, and immunogenicity. Once more suitable production protocols have been developed to resolve these issues it is highly plausible that the advantages of natural polymers could make them superior to synthetic polymers in localized chemotherapy.

As a whole, localized chemotherapy still does not have widespread clinical use, since some concerns still need to be addressed. One challenge of localized drug delivery using polymers is the lack of control in drug distribution. Intravenously delivered chemotherapeutics must overcome barriers including the vasculature wall, and hypoxic tumor regions distant from vasculature may not be exposed to adequate amounts of drug. On the other hand, drug penetration following localized drug delivery is hindered by the extravascular compartment of tumor tissue, which limits drug diffusion to within only 3 mm of the site of origin (Sawyer et al., 2006). Drug diffusion from a polymer matrix depends on the drug gradient in the environment and the tumor’s interstitial fluid pressure, which varies greatly; as a consequence, the drug distribution profile within the tumor becomes somewhat unpredictable. The effectiveness of the drug is compromised if it cannot reach some of the clonogenic cells within a tumor (Minchinton & Tannock, 2006). However, continuous drug release from a polymer matrix allows for the elimination of superficial cells, allowing the drug to reach inner cell layers. The key determinant of overall efficacy is whether chemotherapy eliminates cell layers at a greater rate than tumor cell proliferation. To abrogate the problem of drug penetration, Exner and Saidel (2008) suggest that in situ forming implants should be combined with tumor thermal ablation. In this way, the implant serves to attack residual disease that was not affected by ablation. Localized chemotherapy could also be combined with low-dose systemic administration to increase drug distribution within the tumors.

A great contributor to high interstitial fluid pressure within a tumor is the disorganization and leakiness of existing vasculature (Au et al., 2001). The administration of anti-angiogenic agents has been shown to not only prevent new blood vessel formation, but also normalize existing blood vessels. This reduces vasculature leakiness, thereby reducing interstitial fluid pressure and allowing greater penetration of drugs into the tumor (Exner & Saidel, 2008). In addition, the prevention of new blood vessel formation increases drug retention within the tumor.

Further issues hindering the clinical use of localized chemotherapy include the inability to reach metastatic sites and difficulties in accurate placement during implantation. A possible solution for treating metastatic sites is the use of low-dose systemic chemotherapy in combination with localized chemotherapy. Alternatively, the amount of drug that enters the systemic circulation from the delivery system may be enough to treat metastatic sites, especially if the delivery system has been designed for prolonged release. Although plasma drug levels may be significantly lower than levels resulting from intravenous chemotherapy, prolonged exposure of low-dose chemotherapy has been shown to be clinically beneficial (Vassileva et al., 2007; Zahedi et al., 2009). In terms of accurate placement of the delivery system, imaging modalities have recently proven to be valuable in non-invasively assisting intra-tumoral and peri-tumoral implantation (Exner & Saidel, 2008).

Overall, the principal advantages of localized systems can be attributed to high local drug concentrations at the tumor site for extended periods of time while maintaining low systemic drug exposure. This not only results in higher therapeutic efficacy, lower toxicity, and lower acquired drug resistance (Ho et al., 2006), but also reduces the need for repeat chemotherapeutic administrations, increasing patience compliance and improving quality of life. Further research is necessary to establish methods for accurate and non-invasive implantation into desired sites, means to reach metastatic sites, and to enhance tumor drug penetration upon delivery from polymeric implants. Once these obstacles are overcome, localized chemotherapy via polymeric systems has the potential to greatly improve therapeutic efficacy and toxicity profiles in the treatment of solid tumors.

Declaration of interest

Work in the authors’ laboratories is supported by a research grant obtained from the Canadian Cancer Society, Ontario Division. R. De Souza and P. Zahedi are grateful to the Natural Sciences and Engineering Research Council for post-graduate scholarships. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.