Ultra-High Drug Loading Paclitaxel Dimeric Prodrug Nanoparticles For Cancer Therapy

Paclitaxel(PTX)is a widely used anticancer drug for a number of solid tumors,but it has poor solubility in aqueous solution.Nanoscale formulation for delivery of PTX is a promising approach to increase the solubility and allow drug accumulation in tumor site by virtue of enhanced permeability and retention(EPR)effect.Various polymer-based nanomedicines have been reported for several decades.However,PTX loading contents are usually lower than 20 wt%,which leads to the usage of a large quantity of vectors and potentially heterogeneous formulations.It remains challenging to develop a simple nanoparticle formulation with exceptionally high PTX content to promote chemotherapeutic efficacy and decrease excipient-associated toxicities.Recently,accumulating evidence suggests that organic dimeric molecule is liable to self-assemble into NPs in aqueous solution.Herein,we synthesize a series of PTX dimer prodrugs through suitable derivatives of PTX,and wonder whether the dimeric prodrug technology could play a role on the high-drug-loading,combinational therapy or self-delivery NPs.Besides,enzyme-triggered unit,ROS-cleavable thioketal linker and tumor redox heterogeneity-activated thioether linkage have been integrated into PTX dimer to explore the release behavior of active drug molecule responding to the external and neoplastic stimulus,expecting that it could achieve the maximum antitumor outcome through promoting excellent selectivity towards tumor cells.The primary research are summarized as follows:(1)We synthesize paclitaxel dimer with enzymic and reductive responsive linker through condensation chemistry,which needs a mild reaction condition and simple synthesized process and gives products with definitively controlled structure.As synthesized PTX dimers could form stable nanoparticles in aqueous solution without using any surfactants or adjuvants,and the solubility of PTX in nanoparticles increases by 2500-fold compared to that of free PTX in water.PTX dimers are incorporated into methoxypoly(ethylene glycol)2K-block-poly(D,L-lactide)2K(PEG-PDLLA)micelles for long circulation time,and the loading content of PTX dimers is as high as 85 wt%,which is the first time that ultrahigh drug loading was achieved in the PTX based formulations.The formed nanoparticles possess high stability in biological conditions.Both in vitro and in vivo experiments show that these(PTX dimer)/PEG-PDLLA formulations possess effective cellular uptake and potent cytotoxicity,and exhibit reduced systemic toxicity and enhanced antitumor efficacy towards human cervical tumor.(2)Biomimetic approach offers numerous opportunities to design therapeutic platforms with enhanced antitumor performance and biocompatibility.Herein we report red blood cell membrane-camouflaged nanoparticles(RBC(M(TPC-PTX)))for synergistic chemo-and photodynarmic therapy(PDT).Specifically,the inner core is mainly constructed by reactive oxygen species(ROS)-responsive PTX dimer(PTX2-TK)and photosensitizer 5,10,15,20-tetrapheny lchlorin(TPC).Under appropriate light irradiation,the TPC can generate ROS,not only for PDT but also for triggering PTX2-TK cleavage and on-demand PTX release for chemotherapy.In vivo results show that the coating of RBC membrane enhances the shelter,prolongs blood circulation and improves tumor accumulation,which is the prerequisite for outstanding antitumor performance.The combination of chemo-and photodynamic therapy enhances anticancer therapeutic activity,and light-triggered drug release reduces systematic toxicity.All these characteristics render the described technology extremely promising for cancer treatment.(3)Inspired by the clinically approved albumin based PTX formulation(Abraxane)and high-drug-loading dimeric prodrug tactics,herein we report a theranostic "Abraxane-like" prodrug formulation,which is comprised of human serum albumin(HSA)as steal shell,a paclitaxel dimer(PTX2-S)and photosensitizer IR780 iodide as the core.Compared with HSA-based PTX clinical formulation(Abraxane),the dimeric molecules not only constitute the bulk structure of the particles,but also act as crossing agent,thus realizing drug loading content and excellent stability in biological conditions.Importantly,the thioether linkage dually responds to the tumor redox heterogeneity and the NPs gradually releases the parent drug PTX for chemotherapy.Meanwhile,PTX2-S facilitates the encapsulation of IR780 iodide due to their π-π stacking interaction and IR780 iodide generates spatio-temporal hyperthermia under light irradiation to kill cancer cells for photothermal therapy.