Cellular environmental stimuli-responsive hyaluronan nanocapsules for delivery of anticancer drugs

Abstract

Event Abstract Back to Event Cellular environmental stimuli-responsive hyaluronan nanocapsules for delivery of anticancer drugs Qiangying Yi1, Jin Ma1 and Zhongwei Gu1 1 Sichuan University, National Engineering Research Center for Biomaterials, China Introduction: Owing to the widely existence in extracellular matrix and specific binding affinity for cancer cell over-expressed HA receptor CD 44, hyaluronan (HA) has been extensively studied for potential applications in drug delivery. In this work we propose using of this biocompatible polymer to build up novel anti-cancer drug DOX (Doxorubicin) delivery system possessing environmental stimuli responsive properties. In general, folic acid (FA) terminated hydrophilic zwitterionic tentacles was designed for “stealthy” transportation and targeted delivery of the carriers; specific tumor environmental signals were applied as triggering stimuli to achieve rapid swell up and burst of the carriers, and thereby to realize fast release of encapsulated anti-cancer drugs. For cellular activation, chemical modification is conducted to functionalize the hyaluronan, GSH sensitive crosslinking sites and pH sensitive expansion points are introduced specifically. When the DOX encapsulated nanocapsules arriving at tumor sites, cellular environmental signals would activate exploding of these nanocapsules, generate pulsatile release of the payloads. This drug release pattern could greatly overcome drug resistance of tumor cells and promisingly achieve a better tumor inhibitory effect. Materials and Methods: Photoinitiator 2,2-dimethoxy-2-phenylaceto-phenone (DPAP) was used to initiate free radical thiol-ene coupling reaction of the thiolated HA and Di-ipr-galactopyranose-ene. Poly(carboxybetaine methacrylate) (pCBMA) was introduced to the side chain of thiolated HA via ATRP reaction. Encapsulation of anticancer drug DOX was carried out using the oil-in-water emulsion approach, and formed HA nanocapsules were simultaneously stabilized through ultrasound-mediated thiol to disulfide bond transition. External stimuli activated size change and DOX release from HA nanocapsules were investigated in aqueous buffer solutions with varied pH values and GSH concentrations. The anticancer activity of the DOX-encapsulated HA nanocapules (DOX/HA-NCs) was evaluated both in vitro and in vivo. Results and Discussion: Anticancer drug was successful encapsulated into HA nanocapsules with the DOX content of 6.5% (w/w). Prepared DOX/HA-NCs were observed as shrunk black dots in TEM (~100 nm), while their hydrodynamic diameter of was determined to be 195±53 nm in water. Significant different pH and GSH conditions between tumor and adjacent normal tissue were applied to trigger HA nanocapsule disassembly and thus to promote drug release. In the buffer mimicking tumor cellular environments (pH 5, GSH 10 mM), HA nanocapsules exhibited a 10-fold size swelling in 2 hours and nearly disassembly within 24 hours, whereas these nanocapsules in PBS (pH 7.4, GSH 0) and tumor microenvironment (pH 6.8, GSH 2.8 μM) showed quite better stability. Drug release profiles revealed that release of the encapsulated DOX molecules could be accelerated remarkably (6~10 times) in tumor cellular environment than that in tumor microenvironments and PBS, indicating great potential to fast release vast majority of drugs in tumor tissue. In vivo evaluation showed that zwitterionic tentacles could help the carriers’ safe transportation in circulation and large accumulation in liver tumor sites; DOX-encapsulated nanocapsules exhibited comparable antitumor efficiency and greatly reduced side effect as compared with the free drug DOX. Conclusions: We fabricated HA nanocapsules for delivery of anticancer drug DOX. Prepared nanocapsules demonstrated good stability in storage and also body circulation. Tumor cellular environmental stimuli (pH and GSH) could be applied to stimulate nanocapsule disassembly and drug release. DOX encapsulated HA nanocapsules performed high inhibition efficiency against HepG2 cells. More importantly, in vivo study revealed their comparable antitumor activity and reduced side effect of free DOX. National Natural Science Foundation of China (81471775); Fundamental Research Funds for the Central Universities (2015SCU04A31)