Polymeric conjugates for drug delivery

Abstract

The field of polymer therapeutics has evolved over the past decade and has resulted in the development of polymer-drug conjugates with a wide variety of architectures and chemical properties. Whereas traditional non-degradable polymeric carriers such as poly(ethylene glycol) (PEG) and N-(2-hydroxypropyl methacrylamide) (HPMA) copolymers have been translated to use in the clinic, functionalized polymer-drug conjugates are increasingly being utilized to obtain biodegradable, stimuli-sensitive, and targeted systems in an attempt to further enhance localized drug delivery and ease of elimination. In addition, the study of conjugates bearing both therapeutic and diagnostic agents has resulted in multifunctional carriers with the potential to both "see and treat" patients. In this paper, the rational design of polymer-drug conjugates will be discussed followed by a review of different classes of conjugates currently under investigation. The design and chemistry used for the synthesis of various conjugates will be presented with additional comments on their potential applications and current developmental status.

Figure 1

Rationale for drug delivery via polymer-drug conjugates.

Figure 2

The enhanced permeability and retention or “EPR” effect; increased tumor accumulation of macromolecules occurs via a combination of increased extravasation and reduced lymphatic drainage in tumor tissues.

Figure 3

A) Examples of commercially available functionalized PEGs. B) ENZ-2208, a 40 kDa multiarm PEG conjugate currently under clinical investigation; SN-38 is bound to each PEG arm via a glycine spacer. The use of a multiarm PEG allows a degree of biodegradation and results in higher drug loading (3.7 wt% SN-38) than conjugation to linear PEGs (1.7 wt% SN38). Adapted and reprinted with permission from Ref [21].

Figure 4

Representative structure of PK1 (FCE28068), a HPMA copolymer conjugate bearing the anticancer agent doxorubicin bound via the lysosomally degradable Gly-Phe-Leu-Gly (GFLG) linker (≠). PK1 was the first anticancer polymer-drug conjugate evaluated clinically. Adapted and reprinted with permission from Ref [203].

Figure 5

A) Dendrimers are hyperbranched, star-link polymers. Drugs can be either conjugated to the dendrimer surface or encapsulated within “void” spaces between adjacent branches. B) Dendrimers grow linearly in size and exponentially in surface area with each successive “generation.” They can be utilized as multifunctional nanocarriers, bearing drugs, imaging agents, and/or targeting moieties. C) Synthesis of poly(amido amine) (PAMAM) dendrimers occurs from a ethylenediamine core with alternating reactions with methyl acrylate and ethylenediamine to produce each generation.

Figure 6

A) A typical example of polymeric micelle unimer structure composed of both hydrophilic (mPEG) and hydrophobic (PCL) blocks. Hydrophobic drugs associate with hydrophobic domains of the micelle following self assembly in aqueous conditions. B) Synthetic scheme for mPEG-b-PCL-docetaxel micelle unimer. Adapted and reprinted with permission from Ref [139].

Figure 7

A) Examples of bonds utilized in the synthesis of biodegradable polymer-drug conjugates. Biodegradation typically occurs via hydrolysis (via reduction for disulfides). B) Overall strategy for the synthesis of multiblock polyHPMA copolymers. HPMA copolymer blocks are linked together via lysosomally degradable Gly-Phe-Leu-Gly (GFLG) linkages introduced via a combination of RAFT polymerization and click chemistry. Adapted and reprinted with permission from Ref [81].

Figure 8

A) HPMA copolymer conjugates bearing the antiangiogenic and anticancer agent aminohexylgeldanamycin (AH-GDM) and cyclic Arg-Gly-Asp (RGD) peptides for targeting angiogenic α_vβ₃ integrin expression blood vessels. B) Tumor regression as a function of time in DU145 human prostate cancer tumor bearing nu/nu mice. RGD targeted HPMA copolymers demonstrated significant efficacy as compared to untargeted HPMA copolymers and free drug controls. C) Biodistribution in DU145 bearing mice of ¹²⁵I-radiolabeled HPMA copolymers bearing AH-GDM and cyclic RGD peptides. Increased accumulation was observed in tumor tissues as compared to untargeted conjugate (D). Adapted and reprinted with permission from Refs [82, 83, 195].