Preparation Of Polyphosphoester Based Nanoparticles For Drug Delivery And Cancer Therapy

Polyphosphoesters (PPEs), which were a kind of biodegradable polymer with repeating phosphoester linkages in the backbone, and now, PPEs applied in the field of biological medicine more and more widely.In this paper, we preparaed the hydrophobic PPE block polymers to demonstrate the effect of the state of hydrophobic core on drug release and therapeutic efficacy. Furthermore, we used special interinal environment of tumor site and combined with the characteristics of hydrophobic PPE to achieve delivery of chemotherapy, intracellular stimulus and overcome tumor drug resistance.Firstly, the amphiphilic diblock polymers of poly(ethylene glycol) and polyphosphoester with different side groups (butyl, hexyl, octyl) were synthesized to tune the hydrophobicity of the micellar core. We found that the in vitro cytotoxicity of the DOX-loaded micelles decreased with the increasing hydrophobicity of micellar core due to the drug release rate. However, following systemic delivery, the DOX-loaded micelles with the most hydrophobic core exhibited the most significant inhibition of tumor growth in a MDA-MB-231 tumor model, indicating the importance of hydrophobicity of core on the antitumor efficacy of drug delivery systems.Secondly, to demonstrate the effect of the state of hydrophobic core on therapeutic efficacy, we synthesized an amphiphilic diblock copolymers of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic polyphosphoester, which were viscous flow state at room temperature. The obtained copolymers self-assembled into core-shell nanoparticles, which efficiently encapsulate doxorubicin (DOX) in the hydrophobic polyphosphoester core (NPppe/DOX). As speculated, compared with the nanoparticles bearing glassy core (hydrophobic PLA core, NPpla/DOX), the encapsulated DOX rapidly released from NPPpe/DOX with viscous flow core, resulting in significantly increased cytotoxicity in cancer cells. Accordingly, the improved intracellular drug release from viscous flow core enhances the inhibition of tumor growth, suggesting the nanoparticles bearing viscous flow core show great potential in cancer therapy.Thirdly, he micelles bearing a redox-responsive core composed of PEG and PPE containing disulfide bonds in the side chain was developed to combat MDR. We demonstrated that delivery of doxorubicin (DOX) by the redox-responsive micelles significantly enhanced the drug accumulation and retention in MDR cancer cells by via clathrin and caveolae-dependent endocytosis. In addition, such micelles rapidly released the encapsulated DOX by the reduction of intracellular glutathione. Therefore, the redox micelles not only enhanced the accumulation and retention of DOX but also trigger rapid intracellular drug release, resulting in enhanced the efficiency in overcoming drug resistance of cancer cells in vitro. Moreover, following systemic delivery, the DOX-loaded redox-responsive micelles exhibited significantly enhanced inhibition of tumor growth in a MCF-7/ADR tumor model, indicating that such redox-responsive micelles have great potentials in overcoming MDR for cancer therapy.