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

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.

Figure 1

Examples of localized chemotherapy delivery form factors at various treatment sites and their respective modes of administration.

Figure 2

Synthetic and natural polymers that have been used for localized therapy to malignant tissue.

Figure 3

Polymer-based drug delivery systems for the localized treatment and/or prevention of cancer.

Figure 4

BCNU-loaded Gliadel Wafers implanted intra-cranially into a brain tumor resection cavity [10].

Figure 5

Paclimer microsphere paclitaxel delivery system. A) SEM of microspheres (median diameter = 53 μm), and B) cumulative in vitro release of paclitaxel. (adapted from Harper et. al.[64])

Figure 6

(left) Expansile nanoparticles swell upon exposure to a mildly acidic pH, releasing their payload intracellularly. (right) The nanoparticles localize to tumors following intraperitoneal injection (Ambient image on left and corresponding UV image on right were taken following injection) (adapted from Colson et. al.[71])

Figure 7

Thermosensitive chitosan solution (BST-Gel™) is liquid at room temperature (T_∞) and transitions to a hydrogel at body temperature (37°C). The gel is mixed with drug to deliver chemotherapy intratumorally. (adapted from Ruel-Gariepy et. al.[80])

Figure 8

Oncogel PLGA-PEG-PLGA paclitaxel delivery system. A) cumulative in vitro release of paclitaxel from Oncogel, compared to release from Pluronic, an ethylene glycol/propylene glycol triblock copolymer, and B) injected pancreatic tail w/ arrows identifying Oncogel depot. (adapted from (A) Zentner et. al[85].; (B) Matthes et. al.[86])

Figure 9

Release of Doxorubicin from drug-loaded PLGA millirods implanted into rabbit liver tumor tissue. A) fluorescence image from representative tissue section (millirod located at center of image); B) quantification of drug diffusion from implant. Scale bar = 2 mm. (adapted from Weinberg et. al.[91])

Figure 10

Paclitaxel-loaded poly(glycerol monostearate-co-ε-caprolactone) films prevent local tumor recurrence. A) flexible polymer film coated onto collagen surgical scaffold (scale bar = 5 mm), (B) representative SEM of surgically-stapled film demonstrates good approximation of polymer around staple (scale bar = 100 μm), and (C) prevention of local recurrence with paclitaxel-loaded film compared to intraperitoneal (i.p.), or local paclitaxel injections. (adapted from Liu et. al.[95])

Figure 11

Paclitaxel-loaded poly(glycerol monostearate-co-ε-caprolactone) films A) prevent local tumor recurrence and B) increase median survival in a recurrent sarcoma mouse model. (adapted from Liu et. al.[97])