Multifunctional polymeric micelles for delivery of drugs and siRNA

Abstract

Polymeric micelles, self-assembling nano-constructs of amphiphilic copolymers with a core-shell structure have been used as versatile carriers for delivery of drugs as well as nucleic acids. They have gained immense popularity owing to a host of favorable properties including their capacity to effectively solubilize a variety of poorly soluble pharmaceutical agents, biocompatibility, longevity, high stability in vitro and in vivo and the ability to accumulate in pathological areas with compromised vasculature. Moreover, additional functions can be imparted to these micelles by engineering their surface with various ligands and cell-penetrating moieties to allow for specific targeting and intracellular accumulation, respectively, to load them with contrast agents to confer imaging capabilities, and incorporating stimuli-sensitive groups that allow drug release in response to small changes in the environment. Recently, there has been an increasing trend toward designing polymeric micelles which integrate a number of the above functions into a single carrier to give rise to "smart," multifunctional polymeric micelles. Such multifunctional micelles can be envisaged as key to improving the efficacy of current treatments which have seen a steady increase not only in hydrophobic small molecules, but also in biologics including therapeutic genes, antibodies and small interfering RNA (siRNA). The purpose of this review is to highlight recent advances in the development of multifunctional polymeric micelles specifically for delivery of drugs and siRNA. In spite of the tremendous potential of siRNA, its translation into clinics has been a significant challenge because of physiological barriers to its effective delivery and the lack of safe, effective and clinically suitable vehicles. To that end, we also discuss the potential and suitability of multifunctional polymeric micelles, including lipid-based micelles, as promising vehicles for both siRNA and drugs.

Keywords: micelles; multifunctional; nanocarriers; polymeric; siRNA; targeted.

Figure 1

Micelle formation. Drug-loaded polymeric micelle formed from self -assembly of amphiphilic block copolymers in aqueous media.

Figure 2

Enhanced permeability and retention (EPR) effect and passive targeting. Nanocarriers can extravasate into the tumors through the gaps between endothelial cells and accumulate there due to poor lymphatic drainage.

Figure 3

Drug-loaded polymeric micelles with various targeting functions. (A) Antibody-targeted micelles (B) ligand-targeted micelles (C) Micelles with cell-pentrating function.

Figure 4

A hypothetical multifunctional polymeric micelle. Multifunctional polymeric micelles can be designed to incorporate two or more of these different functions.

Figure 5

Design and construction of targeting-clickable and tumor-cleavable polyurethane nanomicelles. (A) Schematic molecular structure of multiblock polyurethanes; (B) self-assembled clickable polyurethane nanomicelles; (C) conjugation of folate ligand via click chemistry; (D) extracellular pH-activated detachment of PEG shell through the cleavage of benzoic-imine linkage; (E) intracellular drug release triggered by the cleavage of disulfide bond in response to GSH. Reprinted with permission from Song et al. (2013). Copyright © 2013 American Chemical Society.

Figure 6

MMP-2 sensitive nanopreparations. Modified from Zhu et al. (2013). Copyright © 2013 PNAS.

Figure 7

Smart polymeric nanoparticles for mannose receptor-targed cytosolic delivery of siRNA. Schematic representation of the triblock copolymers and formulation into multifunctional nanoscale siRNA delivery vehicles. The blocks include a pH-responsive block that is capable of disrupting endosomes at low pH (red), a cationic block for condensation of nucleic acids (blue), and an azide-displaying block (green) for conjugation of targeting motifs (purple) via click chemistry. Reprinted with permission from Yu et al. (2013b). Copyright © 2013 American Chemical Society.

Figure 8

(A) Schematic illustration of acetal- and TAT-PEO-b-P(CL-g-SP) (I and II) and acetal- and RGD4C-PEO-b-P(CL-Hyd-DOX) (III and IV). (B) Rational design of a multifunctional micellar nanomedicine for targeted co-delivery of siRNA and DOX to overcome multidrug resistance. (a) Chemical structure of functionalized copolymers with ligands at the end of the PEO block and conjugated moieties on the PCL block. (b) Assembly of multifunctional micelles with DOX and siRNA in the micellar core and RGD and/or TAT on the micellar shell. (c) Schematic diagram showing the proposed model for the intracellular processing of targeted micelles in MDR cancer cells after receptor-mediated endocytosis, leading to cytoplasmic siRNA delivery followed by P-gp down-regulation on the cellular and nuclear membrane and endosomal DOX release, followed by DOX nuclear accumulation. Reprinted with permission from Xiong and Lavasanifar (2011). Copyright © 2011 American Chemical Society.

Figure 9

Schematic illustration of formulation of the docetaxel loaded TPGS–siPlk1/TPGS micelles (micSD) and the herceptin-conjugated docetaxel loaded TPGS–siPlk1/TPGS micelles (micSDH). Reprinted from Zhao et al. (2013).

Figure 10

Formation of hierarchical nano-assemblies for combinatorial delivery of siRNA and anticancer drugs. Reprinted from Cao et al. (2011).