Trastuzumab-decorated Multifunctional Polymersomes For Targeted Ovarian Cancer Chemotherapy

In recent years,antibody-drug conjugates(ADCs)have sparked great attention for cancer therapy as a result of their high selectivity and affinity offering precision drug delivery.To date,four ADCs have been marketed and nadcylaTM(Ado-trastuzumab emtansine,T-DM1),as a typical example,has demonstrated significant therapeutic efficacy against HER2-overexpressed metastatic breast cancers.It should be noted,however,the clinically used ADCs including T-DM1 are restricted to toxins only and suffer from low drug content,excessive use of antibody,and high cost.Here,we report on trastuzumab-decorated multifunctional polymersomes for specific delivery of epirubicin hydrochloride(EPI·HC1)and highly potent DM1 to HER2-positive SKOV-3 ovarian tumor.In Chapter 1,trastuzumab based clinical formulations,trastuzumab-modified nanomedicines and disulfide-crosslinked polymeric nanosystems were summarized.In Chapter 2,small-sized,HER2-specific and reduction-sensitive immunopolymersomes(Tra-Ps)with a high loading of EPI-HCl were developed for targeted treatment of SKOV-3 ovarian tumor.Tra-Ps was conveniently obtained via post-conjugation of thiolated trastuzumab on the surface of maleimide-functionalized polymersomes based on maleimide-functionalized poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)(Mal-PEG-P(TMC-DTC))and PEG-P(TMC-DTC)copolymers.EPI·HCl-loaded Tra-Ps(Tra-Ps-EPI)with controllable Tra surface density and a drug loading content of ca.12.7 wt.%showed a small size of 50-60 nm.Interestingly,Tra-Ps with 1.3 trastuzumab on the surface exhibited a 6-fold higher binding affinity to the HER2 extracellular domain than that of native trastuzumab.In vitro studies revealed that Tra-Ps-EPI with long-term storage stability could rapidly release drugs under a reductive condition and efficiently deliver large amount of EPI·HCl to HER2-positive SKOV-3 cells,leading to stronger cytotoxicity than the non-targeted Ps-EPI.Moreover,Tra-Ps-EPI displayed a long circulation time,deep tumor penetration,and superior tumor growth inhibition in SKOV-3 ovarian tumor bearing nude mice,which were more effective than free EPI·HCl and non-targeted Ps-EPI.In Chapter 3,trastuzumab-decorated disulfide-crosslinked polymersomal DM 1 conjugates(Tra-Ps-DM1)were constructed for HER-2 targeted therapy of ovarian cancer.Tra-Ps-DM1 was obtained via simultaneous DM1 conjugation and self-crosslinking during the self-assembly of PEG-P(TMC-DTC)and N3-PEG-P(TMC-DTC),followed by surface modification of trastuzumab through strain promoted click reaction.Tra-Ps-DM1 with 1.4 to 5.7 trastuzumab per Ps exhibited a small size of ca.60 nm and a DM1 to antibody ratio of over 210.Cell experiments indicated that Tra-Ps could efficiently target to HER2-positive SKOV-3 cells with an uptake amount of 23 fold higher than the non-targeting control.Accordingly,Tra-Ps-DM1 showed a 9 fold higher toxicity against SKOV-3 cells than that of Ps-DM1.