Polymer nanostructures synthesized by controlled living polymerization for tumor-targeted drug delivery

Abstract

The development of drug delivery systems based on well-defined polymer nanostructures could lead to significant improvements in the treatment of cancer. The design of these therapeutic nanosystems must account for numerous systemic and circulation obstacles as well as the specific pathophysiology of the tumor. Nanoparticle size and surface charge must also be carefully selected in order to maintain long circulation times, allow tumor penetration, and avoid clearance by the reticuloendothelial system (RES). Targeting ligands such as vitamins, peptides, and antibodies can improve the accumulation of nanoparticle-based therapies in tumor tissue but must be optimized to allow for intratumoral penetration. In this review, we will highlight factors influencing the design of nanoparticle therapies as well as the development of modern controlled "living" polymerization techniques (e.g. ATRP, RAFT, ROMP) that are leading to the creation of sophisticated new polymer architectures with discrete spatially-defined functional modules. These innovative materials (e.g. star polymers, polymer brushes, macrocyclic polymers, and hyperbranched polymers) combine many of the desirable properties of traditional nanoparticle therapies while substantially reducing or eliminating the need for complex formulations.

Figure 1

Design parameters for drug delivery to solid tumors. Drug carriers in circulation (1) are passively targeted to the tumor site by the “enhanced permeability and retention” effect, which encompasses extravasation of the carrier into the tissue via leaky tumor vasculature (2) and prolonged residence due to defective lymphatic clearance. Diffusional barriers often prevent vehicles from penetrating into the tumor tissue (3). Carrier functionalization with “active” targeting ligands can facilitate uptake of drug carriers by cancer cells (4). Finally, release of drug cargo can occur intracellularly or in the extracellular space in response to stimuli such as pH or protease activity (5).

Figure 2

Schematic representation of controlled polymerization methods that have been widely employed to prepare sophisticated polymer architectures for drug delivery.

Figure 3

Schematic representation of advanced macromolecular architectures that are being investigated for drug delivery.

Figure 4

(a) Schematic representation of polymeric brushes synthesized by RAFT and (b) cryoTEM image supporting the pH-induced assembly of these materials into polymersomes. These materials are composed of a methacrylate scaffold from which both hydrophilic poly(ethylene glycol) and endosomolytic poly(DEAEMA_coBMA) (EB) segments radiate. At physiological pH conditions, the hydrophobic (EB) segments induce self-assembly of these materials into polymersomes capable of encapsulating hydrophilic drugs. Subsequent internalization of the polymersomes into acidic intracellular compartments induces disassembly and disruption of the endosomal membrane. Reproduced from Ref. [75] with permission from Polymer Chemistry and The Royal Society of Chemistry.

Figure 5

(a) Schematic representation of 2nd generation brushed-brushes prepared via RAFT polymerization. (b) GPC chromatograms supporting the successful synthesis of 2^nd generation brushed-brushes. The macroCTA shows weak absorbance at 310 nm because of the single trithiocarbonate functionality at the chain end. Grafting of additional RAFT CTAs to the poly(DMA_coHEAm) scaffold significantly enhances the UV absorbance at 310 nm. Following copolymerization of DMA and HEAm a significant shift in elution time is observed supporting the formation of polymeric brushes. The resultant polymer brush was then subjected to a second round of CTA grafting followed by copolymerization of DMA and HEAm to yield well-defined 2^nd generation brushed-brushes. Reproduced from Ref. [90] with permission from Polymer Chemistry and The Royal Society of Chemistry.