作者
Eliézer Jäger,Peter Černoch,Martina Vragović,Lindomar J. C. Albuquerque,Vladimir Sincari,Tomáš Heizer,Alessandro Jäger,Jan Kučka,Olga Janoušková,Ewa Pavlová,Luděk Šefc,Fernando C. Giacomelli
摘要
The aqueous lumen of polymersomes (PSs) can accommodate molecular drugs, enzymes, DNA and RNA fragments. In this regard, stability while navigating complex biological media is a key prerequisite. Nevertheless, the permeability and responsiveness of the polymeric membranes are unquestionably equally relevant and certainly govern the potential bio-related applications of such systems. The polymeric membranes are expected to form a barrier and protect therapeutic agents during systemic circulation. Simultaneously, they are required to regulate the release of the payload at a target location, ideally through a triggered response. Taking these considerations into account, we herein correlate the structural features, permeability and responsiveness behavior of nonresponsive and stimuli-responsive PSs with their in vitro and in vivo antitumor performance. Doxorubicin (DOX)-loaded PSs were produced using amphiphilic block copolymers containing a hydrophilic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) segment linked to poly[N-(4-isopropylphenylacetamide)ethyl methacrylate] (PPPhA, a nonresponsive block), poly[4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)benzyl methacrylate] (PbAPE, a reactive oxygen species (ROS)-responsive block) or to poly[2-(diisopropylamino)ethyl methacrylate] (PDPA, a pH-responsive block). The PDPA-based (pH-responsive) PSs were found to be notably more permeable than the nonresponsive or ROS-responsive assemblies. The fast-triggered release of the DOX payload, particularly at acidic environment, imparts outstanding biological performance to them, with in vivo antitumor activity notably improved compared to the counterparts. Possibly, the selected tumor model may have insufficient ROS concentration, limiting or at least attenuating the rate of ROS-responsive vesicle disassembly. Additionally, the low permeability and nonresponsive nature of the PPPhA block remarkably impact the effectiveness of these potential nanomedicines.