Construction Of Hyaluronic Acid-shelled Nano-polymersomes For Tumor Targeted Chemotherapy

In recent years,polymersomes with unique features including vesicular structure,capacity of loading both hydrophilic and hydrophobic drugs,and tunable membrane property etc.,have received tremendous attention in the tumor targeted chemotherapy.Most of the polymersomal nanomedicines,however,face many challenges such as poor in vivo stability,low tumor accumulation,inefficient cellular uptake,slow intracellular drug release,and poor biodegradability and biocompatibility,which significantly limit their antitumor efficacy and clinical application.To this end,we designed hyaluronic acid(HA)-shelled disulfide-crosslinked biodegradable polymersomes for targeted chemotherapy of CD44 overexpressed MDA-MB-231 breast tumor and further investigated the role of HA density and length on their targeting ability.HA,a biotic and natural polysaccharide,possesses excellent biocompatibility,biodegradability,hydrophilicity and efficient CD44 targetability.In Chapter 2,we designed and prepared novel hyaluronic acid-shelled disulfide-crosslinked polymersomes(HA-XPS)self-assembled from hyaluronic acid-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)diblock copolymer for ultrahigh-efficiency reactive encapsulation and CD44-targeted delivery of mertansine(DM1).HA-XPS showed quantitative encapsulation of DM1 via thiol-disulfide exchange reaction even at a high drug loading content of 16.7 wt.%.DM1 loaded HA-XPS(HA-XPS-DM1)presented a small size of?80 nm(PDI<0.1),robustness with low drug leakage under physiological condition and fast glutathione-triggered drug release.MTT assays revealed that HA-XPS was non-cytotoxic while HA-XPS-DM1 was highly potent to MDA-MB-231 cells with an IC50 comparable to free DM1.The in vitro and in vivo inhibition experiments(Flow cytometry,CLSM and in vivo imaging)indicated that HA-XPS could actively target to MDA-MB-231 cells and followed a receptor mediated uptake pathway.Notably,HA-XPS-DM1 while causing little adverse effects could effectively inhibit tumor growth and significantly prolong survival time in MDA-MB-231 human breast tumor-bearing mice with one mouse became tumor free.In Chapter 3,disulfide-crosslinked polymersomes with different density and length of HA(HA/PEG-XPS)were constructed to explore their targeting ability to CD44-positive MDA-MB-231 cells.HA/PEG-XPS was readily formed via co-selfassembly of PEG-b-P(TMC-co-DTC)and HA-b-P(TMC-co-DTC),wherein,the molecular weight for HA block was 8 and 17 kDa and the density of HA was adjusted by incorporating 10,20 and 30 wt.%HA-b-P(TMC-co-DTC).With increasing HA densities,the size of HA/PEG-XPS became larger and zeta potential became more negative.HA/PEG-XPS could actively load DOX HCl via a pH gradient method with similar loading capacity regardless of HA content.Moreover,the target ability of DOX·HCl loaded HA/PEG-XPS in MDA-MB-231 cells also improved with increasing HA density and molecular weight,for which?3 fold enhanced uptake of DOX HCl-loaded 30%HA17k/PEG-XPS was observed as compared to DOX HCl-loaded PEG-XPS.