Intracellular delivery and antitumor effects of a redox-responsive polymeric paclitaxel conjugate based on hyaluronic acid.

Polymer-drug conjugates have demonstrated application potentials in optimizing chemotherapeutics. In this study a new bioconjugate, HA-ss-PTX, was designed and synthesized with cooperative dual characteristics of active tumor targeting and selective intracellular drug release. Paclitaxel (PTX) was covalently attached to hyaluronic acid (HA) with various sizes (MW 9.5, 35, 770 kDa); a cross-linker containing disulfide bond was also used to shield drug leakage in blood circulation and to achieve rapid drug release in tumor cells in response to glutathione. Incorporation of HA to the conjugate enhanced the capabilities of drug loading, intracellular endocytosis and tumor targeting of micelles in comparison to mPEG. HA molecular weight showed significant effect on properties and antitumor efficacy of the synthesized conjugates. Intracellular uptake of HA-ss-PTX toward MCF-7 cells was mediated by CD44-caveolae-mediated endocytosis. Compared to Taxol and mPEG-ss-PTX, HA9.5-ss-PTX demonstrated improved tumor growth inhibition in vivo with a TIR of 83.27 ± 5.20%. It was concluded that HA9.5-ss-PTX achieved rapid intracellular release of PTX and enhanced its therapeutic efficacy, thus providing a platform for specific drug targeting and controlled intracellular release in chemotherapeutics. Polymer-drug conjugates, promising nanomedicines, still face some technical challenges including a lack of specific targeting and rapid intracellular drug release at the target site. In this manuscript we designed and constructed a novel bioconjugate HA-ss-PTX, which possessed coordinated dual characteristics of active tumor targeting and selective intracellular drug release. Redox-responsive disulfide bond was introduced to the conjugate to shield drug leakage in blood circulation and to achieve rapid drug release at tumor site in response to reductant like glutathione. Paclitaxel was selected as a model drug to be covalently attached to hyaluronic acid (HA) with various sizes to elucidate the structure-activity relationship and to address whether HA could substitute PEG as a carrier for polymeric conjugates. Based on a series of in vitro and in vivo experiments, HA-ss-PTX performed well in drug loading, cellular internalization, tumor targeting by entering tumor cells via CD44-caveolae-mediated endocytosis and rapidly release drug at target in the presence of GSH. One of the key issues in clinical oncology is to enhance drug delivery efficacy while minimizing side effects. The study indicated that this new polymeric conjugate system would be useful in delivering anticancer agents to improve therapeutic efficacy and to minimize adverse effects, thus providing a platform for specific drug targeting and controlled intracellular release in chemotherapeutics.

Yin S ，Huai J ，Chen X ，Yang Y ，Zhang X ，Gan Y ，Wang G ，Gu X ，Li J ... -  《-》

Biological evaluation of redox-sensitive micelles based on hyaluronic acid-deoxycholic acid conjugates for tumor-specific delivery of paclitaxel.

Tumor-targeted drug delivery and microenvironment-responsive drug release are attractive strategies in cancer treatment. Our previous study demonstrated that redox-sensitive micelles based on hyaluronic acid-deoxycholic acid (HA-ss-DOCA) conjugates exhibited excellent drug-loading capacities (34.1%) for paclitaxel (PTX) and rapid drug release in response to reducing agent, glutathione. In the present study, the physicochemical and biological properties of PTX-loaded HA-ss-DOCA (PTX-HA-ss-DOCA) micelles were investigated further. The micelles have an average size of about 120 nm and a zeta potential of about -36 mV. Transmission electron microscopy and wide-angle X-ray diffraction analysis demonstrated redox-sensitive degradation of micelles in the presence of glutathione. Moreover, the encapsulated payload was effectively released from HA-ss-DOCA micelles into cytoplasm and then rapidly transported into nuclei. In vitro cytotoxicity and cell apoptosis assay further revealed that HA significantly improved the tumor-specific drug delivery of HA-ss-DOCA micelles via receptor-mediated endocytosis, while efficient intracellular drug release and transportation lead to marked inhibition of tumor cell growth, as compared to Taxol(®) and insensitive micelles. More importantly, PTX-HA-ss-DOCA micelles demonstrated superior in vivo antitumor activity compared with Taxol(®) and insensitive control, and decreased systemic toxicity. Herein we present data which provide valuable insight into the design and development of tumor-specific drug delivery systems.

Li J ，Yin T ，Wang L ，Yin L ，Zhou J ，Huo M ... -  《-》

Trimethyl chitosan based conjugates for oral and intravenous delivery of paclitaxel.

Paclitaxel (PTX) conjugated trimethyl chitosan (TMC-PTX) and folic acid (FA) modified TMC-PTX (FA-TMC-PTX) were developed as polymer-drug conjugates for oral and intravenous delivery of PTX. As amphiphilic conjugates, TMC-PTX and FA-TMC-PTX containing approximately 11wt% PTX could self-assemble into spherical nanoparticles with average sizes of 170 and 187nm, respectively. The conjugates presented a sustained release of PTX and the release rate was positively correlated with the pH value of medium ranging from 1.2 to 7.4. TMC-PTX and FA-TMC-PTX possessed enhanced mucoadhesion compared with trimethyl chitosan, and promoted ex vivo intestinal transport of PTX in comparison to PTX solution by 15.5 and 18.8 folds, respectively. Hemolysis assessment confirmed the safety of TMC-PTX and FA-TMC-PTX, and FA modification alleviated protein adsorption of the conjugates. Prolonged blood retention and increased PTX accumulation in the tumor were achieved for orally and intravenously administered conjugates. In H22 tumor-bearing mice, TMC-PTX delivered via oral or intravenous route showed superior tumor retardation and survival rate compared with intravenously injected PTX, and FA-TMC-PTX further enhanced the antitumor efficacy. Overall, the trimethyl chitosan based drug conjugates may have potential applications as a promising candidate for cancer therapy. In the current study, PTX conjugated trimethyl chitosan (TMC-PTX) and folic acid (FA) modified TMC-PTX (FA-TMC-PTX) were developed as the polymer-drug conjugates for oral and intravenous delivery of PTX. By exploiting advantages with respect to improved solubility of drugs, controlled release behavior of covalently linked drugs, and enhanced targeting effect towards tumors, improved tumor growth inhibition efficacy and prolonged survival time were achieved for TMC-PTX as compared with free PTX, and FA modification further enhanced the in vivo antitumor efficacy. Overall, the self-assembled nanoplatform of trimethyl chitosan based drug conjugates may have potential applications as a promising candidate for tumor therapy via different administration routes.

He R ，Yin C 《-》

Investigation on vitamin e succinate based intelligent hyaluronic acid micelles for overcoming drug resistance and enhancing anticancer efficacy.

Multidrug resistance (MDR) is a major reason for anticancer chemotherapy failure, and P-glycoprotein (P-gp) over-expressing on tumor cells is considered as the important target to overcome MDR. Emerging reports have showed that vitamin E (VE) can cause significant reversal of MDR due to inhibition of ATPase activity. Accordingly, we synthesized hyaluronic acid (HA) conjugated vitamin E succinate (VES) polymer, which can self-assemble into micelles and thus achieve high drug (paclitaxel (PTX) used as model drug) encapsulation as well as tumor accumulation owing to the enhanced permeability and retention (EPR) effect and HA active targeting ability. In addition, the linker between HA and VES utilized in this work was disulfide bond with reduction-sensitive property, which would respond to high glutathione (GSH) concentration in tumor cytoplasmic environment and trigger HA-CYS-VES polymer disassociation and drug release. In vitro, PTX loaded HA-CYS-VES demonstrated enhanced cytotoxicity, high apoptosis-inducing activities and reversal effects of PTX on MCF-7/Adr cells, compared to PTX. Also, cellular uptake and intracellular PTX accumulation tests displayed that PTX loaded HA-CYS-VES could more efficiently enter tumor cells and selectively release drug in cytosol so as to facilitate its function on microtubule. More importantly, PTX loaded HA-CYS-VES showed better tumor targeting ability, improved antitumor efficacy and low adverse effects on tumor-bearing mice. In conclusion, PTX loaded HA-CYS-VES exhibited a great potential for reversing MDR in anticancer chemotherapeutics.

Hou L ，Tian C ，Chen D ，Yuan Y ，Yan Y ，Huang Q ，Zhang H ，Zhang Z ... -  《-》

Well-Defined Redox-Sensitive Polyethene Glycol-Paclitaxel Prodrug Conjugate for Tumor-Specific Delivery of Paclitaxel Using Octreotide for Tumor Targeting.

Yin T ，Wu Q ，Wang L ，Yin L ，Zhou J ，Huo M ... -  《-》