IntroductionMultidrug resistance (MDR) of breast cancer is the major challenge to successful chemotherapy while mitochondria-targeting therapy was a promising strategy to overcome MDR.Materials and methodsIn this study, HER-2 peptide-PEG2000-Schiff base-cholesterol (HPSC) derivate was synthesized successfully and incorporated it on the surface of the doxorubicin (DOX)-loaded dequalinium (DQA) chloride vesicle (HPS-DQAsomes) to treat drug-resistant breast cancer. Evaluations were performed using human breast cancer cell and DOX-resistant breast cancer cell lines (MCF-7 and MCF-7/ADR).ResultsThe particle size of HPS-DQAsomes was ~110 nm with spherical shape. In vitro cytotoxicity assay indicated that HPS-DQAsomes could increase the cytotoxicity against MCF-7/ADR cell line. Cellular uptake and mitochondria-targeting assay demonstrated that HPS-DQAsomes could target delivering therapeutical agent to mitochondria and inducing mitochondria-driven apoptosis process. In vivo antitumor assay suggested that HPS-DQAsomes could reach favorable antitumor activity due to both tumor targetability and sub-organelles’ targetability. Histological assay also indicated that HPS-DQAsomes showed a strong apoptosis-inducing effect. No obvious systematic toxicity of HPS-DQAsomes could be observed.ConclusionIn summary, multifunctional HPS-DQAsomes provide a novel and versatile approach for overcoming MDR via mitochondrial pathway in cancer treatment.

The therapeutic efficacy of chemotherapy is dramatically hindered by multidrug resistance (MDR), which is induced by the overexpression of P-glycoprotein (P-gp). The codelivery of an antitumor drug and siRNA is an effective strategy recently applied in overcoming P-gp-related MDR. In this study, a multifunctional drug delivery system with both pH-sensitive feature and active targetability was designed, in which MDR1-siRNA and DOX were successfully loaded. The resulting carrier EphA10 antibody-conjugated pH-sensitive doxorubicin (DOX), MDR1-siRNA coloading lipoplexes (shortened as DOX + siRNA/ePL) with high serum stability had favorable physicochemical properties. DOX + siRNA/ePL exhibited an incremental cellular uptake, enhanced P-gp downregulation efficacy, as well as a better cell cytotoxicity in human breast cancer cell line/adriamycin drug-resistant (MCF-7/ADR) cells. The results of the intracellular colocalization study indicated that DOX + siRNA/ePL possessed the ability for pH-responsive rapid endosomal escape in a time-dependent characteristic. Meanwhile, the in vivo antitumor activities suggested that DOX + siRNA/ePL could prolong the circulation time as well as specifically accumulate in the tumor cells via receptor-mediated endocytosis after intravenous administration into the blood system. The histological study further demonstrated that DOX + siRNA/ePL could inhibit the proliferation, induce apoptosis effect, and downregulate the P-gp expression in vivo. Altogether, DOX + siRNA/ePL was expected to be a suitable codelivery system for overcoming the MDR effect.

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A stimuli-responsive nanoplatform achieves successful intracellular siRNA delivery due to a proton sponge effect based on poly(l-histidine) and effective gene silencing in vivo.

There are two severe obstacles in cancer immunotherapy. The first is that the low response rate challenges the immune response owing to the immunosuppressive tumor microenvironment (ITM) and poor immunogenicity of the tumor. The second obstacle is that the dense and intricate pathophysiology barrier seriously restricts deep drug delivery in solid tumors. A laser/glutathione (GSH)-activatable nanosystem with tumor penetration for achieving highly efficient immunotherapy is reported. The core of the nanosystem was synthesized by coordinating zinc ions with GSH-activatable oxaliplatin (OXA) prodrugs and carboxylated phthalocyanine. Such an OXA/ phthalocyanine-based coordination polymer nanoparticle (OPCPN) was wrapped by a phospholipid bilayer and NTKPEG. NTKPEG is a PEGylated indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor prodrug containing a thioketal (TK) linker, which was modified on the OPCPN (OPCPN@NTKPEG). Upon the laser irradiation tumor site, ROS production of the OPCPN@NTKPEG triggers cleavage of NTKPEG by degradation of TK for promoted tumor penetration and uptake. OXA, phthalocyanine, and IDO1 inhibitor were released by the intracellular high-level GSH. OXA inhibits cell growth and is combined with photodynamic therapy (PDT) to induce immunogenic cell death (ICD). The IDO1 inhibitor reversed the ITM by suppressing IDO1-mediated Trp degradation and exhaustion of cytotoxic T cells. Laser/GSHactivatable drug delivery was more conducive to enhancing ICD and reversing ITM in deep tumors. Chemo-PDT with OPCPN@ NTKPEG significantly regressed tumor growth and reduced metastasis by improved cancer immunotherapy.