Review
Local drug delivery strategies for cancer treatment: Gels, nanoparticles, polymeric films, rods, and wafers

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Abstract

Polymer-based drug delivery depots have been investigated over the last several decades as a means to improve upon the lack of tumor targeting and severe systemic morbidities associated with intravenous chemotherapy treatments. These localized therapies exist in a variety of form factors designed to facilitate the delivery of drug directly to the site of disease in a controlled manner, sparing off-target tissue toxicities. Many of these depots are biodegradable and designed to maintain therapeutic concentrations of drug at the tumor site for a prolonged period of time. Thus a single implantation procedure is required, sometimes coincident with tumor excision surgery, and thereby biodegrading following complete release of the loaded active agent. Even though localized polymer depot delivery systems have been investigated, a surprisingly small subset of these technologies has demonstrated potentially curative preclinical results for cancer applications, and fewer have progressed toward commercialization. The aims of this article are to review the most well-studied and efficacious local polymer delivery systems from the last two decades, to examine the rationale for utilizing drug-eluting polymer implants in cancer patients, and to identify the patient cohorts that could most benefit from localized therapy. Finally, a discussion of the physiological barriers to localized therapy (i.e. drug penetration, transport), technical hurdles, and future outlook of the field is presented.

Graphical abstract

Polymer-based treatment strategies for localized drug delivery in cancer applications include, for example, intratumoral injection of thermogel or nano/micro-particles to inhibit tumor growth or placement of films along tumor resection margins to prevent tumor recurrence.

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Introduction

Polymer-based drug delivery systems have been investigated over the last few decades as a means of achieving high therapeutic concentrations of chemotherapy to the site of malignant disease in cancer patients [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. The development of these technologies is guided by the desire to improve overall survival and quality of life by increasing the bioavailability of drug to the site of disease, containing delivery to the cancerous tissues, increasing drug solubility, and minimizing systemic side effects. Existing systems can be divided into two groups based on their mode of administration and mechanism of action. The first relies on systemic delivery and consists of nano-materials such as polymer nanoparticles, liposomes, and dendrimers. These delivery vehicles find their target by localization to solid tumors by passive diffusion via leaky tumor vasculature, active targeting by conjugation to a chemical moiety with an affinity for an over-expressed/unique tumor cell marker (i.e. folic acid receptor, monoclonal antibody, etc.), or by triggering the release of payload from an environment-responsive nano-carrier using a local stimulus (i.e. pH, temperature, etc.). These nano-materials are predominantly intended for intravenous administration, and, while they promise the ability to target tumor tissues with accumulation of therapeutic concentrations of drug, localization is challenging due to removal and sequestration of these nanomaterials by the reticuloendothelial system. Additionally, there is a recognized need for development and validation of nano-toxicity characterization methods for obtaining reliable predictive safety information [11].

The second group of polymer delivery vehicles (and focus of this review) includes controlled release drug delivery depot systems for implantation intra-tumorally or adjacent to the cancerous tissue (Fig. 1). These technologies have been embodied in a variety of form-factors such as drug-eluting films, gels, wafers, rods, and particles and feature predictable and prolonged drug release kinetics. The majority of these devices are biodegradable so as to circumvent a second surgery for device removal and to avoid a chronic foreign-body immune response. The polymers used in these systems can be broadly divided into natural and synthetic materials. Natural polymers that have been investigated for drug delivery applications include polysaccharides such as alginate [12], [13], [14], hyaluronic acid [15], dextran [16] and chitosan [17], [18], [19] and polypeptides including collagen [20], albumin [21], [22], elastin [23], and gelatin [24], [25]. These materials are tolerated well in vivo, are available in abundance in nature, and can form hydrogels via self-assembly or by cross-linking. Furthermore, the property of spontaneous hydrogel formation of some natural polymers has been exploited to develop smart delivery vehicles that can be injected locally as a liquid, and upon exposure to changes in environment such as temperature, pH, or ionic composition, solidify into a hydrogel drug depot. Drawbacks of these materials include: 1) a necessity for high purity for biocompatibility, 2) poor solubility, particularly in organic solvents, restricting processing options and complicating the inclusion of water-insoluble chemotherapy agents, and 3) limited opportunity for chemically tuning polymer compositions to affect key properties such as drug release kinetics and degradation rate.

Conversely, the degree of customization achievable with synthetic polymers allows the application-specific design of local implants with respect to degradation, drug release, and mechanical properties. A wide range of delivery materials have been fabricated using polyesters based on lactide, glycolide, caprolactone, and dioxanone, polyanhydrides based on sebacic and adipic acid, as well as polyamides, polycarbonates, polyorthoesters, and phosphate-based polymers, which have been reviewed in detail elsewhere [7], [9], [10], [26], [27], [28]. These polymers are often hydrophobic in nature, and are ideally suited for long-term delivery and internal stabilization of sensitive water-insoluble drugs. A significant drawback to synthetic materials is that many form acidic degradation products that can accumulate and cause inflammation at the implant site. However, this effect can be mitigated via adjustments in chemical composition and degradation profile. The aims of this article are to review the most well-studied and efficacious local polymer delivery systems from the last two decades, to examine the rationale for utilizing drug-eluting polymer implants in cancer patients, and to identify the patient cohorts that could most benefit from localized therapy.

Section snippets

The clinical need for localized cancer therapy

The lifetime probability of developing an invasive cancer is 44% for men and 38% for women resulting in an estimated 1,529,560 cancer diagnoses and 569,490 deaths in the US in 2010 [29]. Treatment is dictated by the cancer type, stage at diagnosis, and the patient's tolerance to the prescribed therapy. Tumors are normally classified by the TNM staging system (tumor, node, distant metastasis) which describes the extent to which the cancer has spread. Staging can be broadly divided into early,

Gliadel Wafer

The Gliadel Wafer (MGI Pharma/Easai Pharmaceuticals) is perhaps the most-well studied and successful drug delivery implant for the treatment of recurrent brain cancer. Developed in the early 1980's by Langer and Brem, this technology has been reviewed from its chemistry and mechanistic aspects of drug release to its performance across multiple clinical trials [58], [59], [60]. The highlights of this technology will be outlined briefly to allow comparison to other technologies in this review.

The

Paclimer microspheres

Paclimer microspheres are a microparticle technology intended for intraperitoneal administration and ultimately prevention of recurrent ovarian cancer. Developed in part by Guilford Pharmaceuticals, the use of Paclimer has demonstrated modest success in vivo leading to a Phase 1 clinical trial. Paclimer microparticles consist of a sustained-release formulation of paclitaxel-loaded (10% wt/wt) polyphosphoester particles. Harper et al. reported the first formulation and in vivo assessment of

Expansile nanoparticles

Expansile nanoparticles have been designed to release their drug payload upon exposure to an environmental trigger, thus focusing the delivery of drug at the treatment site and minimizing systemic exposure. Their utility has been demonstrated successfully in two tumor models: lung cancer [69], and mesothelioma [70], [71].

Griset et al. reported the use of a novel nanoparticle polymer composition (100 nm diameter) for the prevention of lung tumor growth [69]. Upon exposure to a pH of 5 or lower,

Chitosan hydrogels

Chitosan is a linear cationic polysaccharide derived from the shells of crustaceans (e.g. crabs and shrimp) that has found various uses in biomedical applications due to its reported biodegradation and biocompatibility [77]. Chitosan is produced by the deactylation of chitin, and has been used clinically in applications such as suture and wound healing materials [78]. The material has been investigated as a drug delivery system in the form of microparticles, nanoparticles, hydrogels, and films

Oncogel

Paclitaxel formulations of a poly(lactide-co-glycolide) and polyethylene glycol) tri-block copolymer(PLGA-PEG-PLGA), also known as ReGel and manufactured under the trade name OncoGel, have been assessed in vivo to evaluate efficacy in local tumor management [85]. The ReGel system is a thermosensitive, water-soluble implant comprised of an aqueous solution of biocompatible polymers. Similar to the BST-gel chitosan technologies described earlier, ReGel solutions are designed to undergo a

Polymer millirods

The use of chemotherapy-loaded polymer millirod implants to supplement the treatment of tumors with radio-frequency (RF) ablation in an effort to reduce local recurrence rates has also been actively studied. Tumor recurrence is greatest at the periphery of the ablation zone and around blood vessels where residual tumor cells remain. It is hypothesized that drug eluted from an implant placed at the center of an ablation region will undergo enhanced tissue penetration, in part due to destroyed

Flexible film composites

One particular challenge to local delivery along soft tissue surgical resection margins is administration—achieving adequate surface coverage, fixation, and drug diffusion within the tissue at highest risk for local recurrence. The irregular shape of soft tissues after surgery precludes the use of rigid polymers in most cases, such that other strategies must be employed to provide a flexible, drug-eluting material. While methods such as coating the tissue surface with a polymerizable hydrogel

Drug penetration considerations

Local administration of polymer-based devices ensures high levels of anticancer agents at the site of disease, but the efficacy of these treatments depends upon the accessibility of the delivered therapeutic agent to the tumor and nearby diseased tissue. Adequate diffusion to reach sites harboring occult tumor cells is paramount to preventing recurrence. For instance, lung cancer patients suffer from a 2-fold increase in locoregional recurrence following smaller “wedge” resections (17–24%)

Existing challenges and future outlook

The current standard of care for most primary or recurrent cancers utilizes single or multi-modal combinations of surgery, chemotherapy, and/or radiation depending on the tumor location and patient co-morbidities. The use of chemotherapy for treatment of localized tumor is mostly used as an adjuvant to surgery to protect against or delay the progression of disseminated metastatic disease, or for treatment when other local therapies, such as surgery, are not available. Compared to systemic

Acknowledgement

This work was supported in part by BU, BWH, CIMIT, NSF DMR-1006601, NIH R01CA149561, and the Boston University's Nanomedicine Program and Cross-Disciplinary Training in Nanotechnology for Cancer, NIH R25 CA153955.

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