Biodegradable Stimuli-Responsive Polymeric Micelles for Treatment of Malignancy

Abstract

In the past decade, drug delivery systems that can respond to the tumor microenvironment or external stimuli have emerged as promising platforms for treating malignancies due to their improved antitumor efficacy and reduced side effects. In particular, biodegradable polymeric micelles have attracted increasing attention and been rapidly developed as a distinct therapeutic to overcome limitations of conventional chemotherapeutic anticancer drugs. Because of their advantages with respect to biocompatibility, degradability, circulation time, and tumor accumulation, considerable effort has been dedicated to the developing and optimizing micellar systems during the past few years. This review highlights recent advances concerning stimuli-responsive micelles made of biodegradable polypeptide and polyester as nanocarries for drug delivery, and especially limits the content to pH sensitive, redox sensitive, and photo-sensitive micellar systems for safe and efficient cancer chemotherapy.

Fig. 1

DOX-loaded zwitterionic polymer-based micelles change their surface properties in response to tumor extracellular pH. (1) PCL-b-P(AEP-g-TMA/DMA), an amphiphilic zwitterionic block copolymer, assembles into micelles and encapsulates DOX at pH 7.4. The micelles are of appropriate size to take advantage of tumors’ enhanced permeability and retention effect in vivo. (2) When the extracellular pH decreases to 6.8, as in the tumor extracellular environment, DMA is cleaved from the anionic component of the polymer, forming PCL-b-P(AEP-g-TMA/Cya). The resulting micelles are positively charged and are more readily taken up by tumor cells. Reproduced with permission [26]. Copyright 2012, Wiley-VCH.

Fig. 2

Dual pH-responsive polymer-Dox conjugates (mPEG-b-PAEP-Cya-Hyd-DOX-DA) self-assemble into negatively charged micelles in water (1). When the micelle is exposed to the acidic tumor microenvironment (pH ~6.8), the negatively-charged portion of the polymer is cleaved off, revealing an amine group and rendering the particles positively charged (2). The positively charged micelles are more readily endocytosed by tumor cells (3, 4) and accumulate in endolysosomal compartments within the cell. At the even more acidic pH of endolysosomes (~5.5), the hydrazone bond is cleaved to release DOX, which diffuses into the nucleus of the cell (5). Reproduced with permission from Reference [54]. Copyright 2012, American Chemical Society.

Fig. 3

Schematic showing the formation of and drug release from cross-linked mPEG-b-P(LA-co-MTC_SH) micelles. Reproduced with permission from Reference [70]. Copyright 2011, Royal Society of Chemistry.

Fig. 4

(A) Dual-sensitive interlayer-cross-linked micelles (HP-ICM) can be assembled from mPEG-PAsp(MEA)-PASM(DIP) with DOX loading at pH 7.4, and are stable up to pH 10. However, at pH 5.0 or under reducing conditions (DTT), the micelles rapidly disintegrate to release DOX. (B) Release profile of DOX from HP-ICM at various pH and reducing conditions. (C) Cellular uptake of DOX delivered as free drug, HP-ICM, and control PEG-PCL micelles. (D) Fluorescence images showing in vivo accumulation of DOX into tumor-bearing nude mice. DOX-loaded HP-ICM passively accumulate in the tumor. (a) Tumor growth inhibition is greatest when DOX-loaded HP-ICM are injected via tail vein, compared to controls (b). Reproduced with permission from Reference [73]. Copyright 2011, Wiley-VCH.