Optimizing Hydrophobic Groups in Amphiphiles to Induce Gold Nanoparticle Complex Vesicles for Stability Regulation

Polymeric graft polyphosphazene containing 4-aminobenzoic acid diethylaminoethyl ester (DEAAB) as hydrophobic side groups was rationally designed and named PDEP. PDEP can self-assemble into a nanovesicle in water. More importantly, when compared with the amphiphile poly­[(methoxy-poly­(ethylene glycol))­(ethyl p-amino­benzoate)]­phosphazene (PEP) copolymer containing benzene rings and the amphiphile poly­[(methoxy-poly­(ethylene glycol)­(N,N-diisopropyl­ethylenedi­amine)]­phosphazene (PDP) copolymer containing tertiary amino groups, the coexistence of benzene and tertiary amino groups in PDEP enabled it to effectively load water-soluble small-molecule doxorubicin hydrochloride (DOX·HCl) into the vesicle and efficiently induce in situ transformation of gold tetrachloroaurate (HAuCl₄) to gold nanoparticles (AuNPs) as both a reductant and a stabilizer. By optimizing the reduction conditions, such as the temperature, reaction time, and hydrophobic group in polymer/HAuCl₄ molar ratio, the AuNP complex PDEP vesicles significantly inhibited the DOX·HCl burst release at pH 7.4 while displaying a fast release responsive to pH 5.5

Design of pH-Sensitive Nanovesicles via Cholesterol Analogue Incorporation for Improving in Vivo Delivery of Chemotherapeutics

pH-responsive polymersomes have emerged as promising nanocarriers for antitumor drugs to realize their fast release and action in a weakly acidic microenvironment of tumor cells. Herein, however, we designed a remarkably pH-responsive polymersome self-assembled from amphiphilic benzimidazole-based polyphosphazenes via the incorporation of cholesteryl hemisuccinate (CholHS), a type of cholesteric molecule, into the polymersome bilayers to inhibit the drug release during blood circulation. Actually, unwanted premature drug leakage before arriving at the acidic tumor site has become a serious problem for polymersomes encapsulating water-soluble drugs, especially when the drug loading is at a high level, thus limiting the therapeutic efficacy. In this study, polymersomes displayed high loading capability of doxorubicin hydrochloride as 12.83%. More importantly, CholHS incorporation decreased the membrane permeability of the polymersome and effectively retarded the cargo release under physiological conditions but induced the fast drug-release rate at pH 5.5, demonstrating a more remarkably acid-responsive release behavior when compared to that of the CholHS-free polymersomes. Further in vivo investigations including pharmacokinetic and antitumor activity studies verified the extended circulation time and enhanced antitumor efficacy of the drug-loaded CholHS-incorporated polymersomes

Polymersomes via Self-Assembly of Amphiphilic β‑Cyclodextrin-Centered Triarm Star Polymers for Enhanced Oral Bioavailability of Water-Soluble Chemotherapeutics

To date, improving oral bioavailability of water-soluble drugs with poor membrane permeability is still challenging. An example of this includes doxorubicin hydrochloride (DOX·HCl), a widely used chemotherapeutic. We therefore developed a novel DOX·HCl-loaded polymersome (Ps-DOX·HCl) self-assembled by amphiphilic β-cyclodextrin-centered triarm star polymer (mPEG^2k-PLA^3k)₃-CD with the considerable drug loading capability. Using Madin-Darby canine kidney (MDCK) cells trans-well models, it was found that the cellular uptake and absorptive transport of DOX·HCl was significantly increased and the efflux was attenuated when delivered through polymersomes than free drugs. This phenomenon was further verified in mechanistic studies, which was attributed to the change in membrane transport pathway from paracellular route (free DOX·HCl) to active transcellular transport (drug-loaded polymersomes). Moreover, in vivo pharmacokinetic studies in mice demonstrated a significant increase in the oral bioavailability of Ps-DOX·HCl compared with free DOX·HCl (7.32-fold), as well as extended half-life (8.22-fold). This resulted in a substantial anticancer efficacy against mouse sarcoma 180 (S180) tumor in vivo. The cardiotoxicity, which is intrinsically induced by DOX·HCl, and toxicity toward gastrointestinal tissues were avoided according to histological studies. These findings indicate that (mPEG^2k-PLA^3k)₃-CD copolymer displays great potential as a vehicle for the effective oral delivery of water-soluble drugs with low permeability

Cationic Polyphosphazene Vesicles for Cancer Immunotherapy by Efficient in Vivo Cytokine IL-12 Plasmid Delivery

To circumvent the severe toxicity of the systemic delivery of IL-12 protein and the limits of local administration of IL-12 gene, we constructed a polymersome system for systemic delivery of recombinant murine IL-12 plasmid (pmIL-12) based on amphiphilic polyphosphazenes containing weakly cationic N,N-diisopropylethylene­diamine (DPA) as hydrophobic groups and monomethoxy poly­(ethylene glycol) (mPEG) as hydrophilic tails. By simple dialysis method, pmIL-12 was successfully loaded into polymersomes due to the combination effect of physical encapsulation and electrostatic interaction. This pmIL-12 polymersome delivery system was validated with good biocompatibility and stability despite of serum protein and DNase challenging. The results of in vivo antitumor experiments showed that intravenous injection of pmIL-12 polymersomes achieved significant suppression of tumor growth in BALB/c mice bearing CT-26 colon carcinoma. The analysis revealed that the mechanism was related to the antitumor immune response induced by efficient transfection of pmIL-12 polymersomes, which maybe involved lymphocytes infiltration and angiogenic inhibition at the tumor site