A ROS-responsive polymeric prodrug nanosystem with self-amplified drug release for PSMA (-) prostate cancer specific therapy.

BACKGROUND: The selectively accumulate in tumor site and completely release drug within cancer cells great limit the therapeutic effect of nano-drug delivery system. Moreover, absence of appropriate biomarker is one of the major challenges for prostate specific membrane antigen negative (PSMA (-)) prostate cancer therapy. RESULTS: Herein, a PSMA (-) prostate cancer specific targeted and intracellular reactive oxygen species (ROS) amplification for ROS-responsive self-accelerating drug release nanoplatform (ATD-NPs) was developed. ATD-NPs was formed by three parts, including PSMA (-) prostate cancer specifically targeted part (DUP-PEG-DSPE), ROS-sensitive doxorubicin (DOX) polymeric prodrug (P(L-TK-DOX)), and the ROS generation agent (α-tocopheryl succinate, α-TOS); and this delivery system is expected to enhance PSMA (-) prostate cancer therapeutic effect, increase selective accumulation at tumor site and overcome intracellular incomplete drug release. After administration i.v injection, ATD-NPs could specifically accumulate in tumor site and markedly be internalized by cancer cells based on the DUP-1 (a PSMA (-) cancer cells specific target peptide). Subsequently, ATD-NPs could be dissociated under the high concentration reactive oxygen species (ROS) condition, resulting in DOX and α-TOS release. Then, the released α-TOS could be reacted with mitochondria to produce ROS, which in turn accelerating the release of drugs. Finally achieved the purpose of enhancing therapeutic efficacy and reducing side effect. Both in vitro and in vivo experiments demonstrated that the combination of tumor actively-targeted and self-amplifying ROS-responsive drug release showed more significant antitumor activity in the human PSMA (-) prostate cancer. CONCLUSION: The described technology unifies the tumor actively targets, self-amplified drug release, and excellent biocompatibility into one formulation, are promising for cancer treatment.

Hyaluronic acid reduction-sensitive polymeric micelles achieving co-delivery of tumor-targeting paclitaxel/apatinib effectively reverse cancer multidrug resistance.

Multidrug resistance (MDR) of cancer cells is a significant challenge in chemotherapy, highlighting the urgent medical need for simple and reproducible strategies to reverse this process. Here, we report the development of an active tumor-targeting and redox-responsive nanoplatform (PA-ss-NP) using hyaluronic acid-g-cystamine dihydrochloride-poly-ε-(benzyloxycarbonyl)-L-lysine (HA-ss-PLLZ) to co-deliver paclitaxel (PTX) and apatinib (APA) for effective reversal of MDR. This smart nanoplatform specifically bound to CD44 receptors, leading to selective accumulation at the tumor site and uptake by MCF-7/ADR cells. Under high concentrations of cellular glutathione (GSH), the nanocarrier was degraded rapidly with complete release of its encapsulated drugs. Released APA effectively inhibited the function of the P-glycoprotein (P-gp) drug pump and improved the sensitivity of MDR cells to chemotherapeutic agents, leading to the recovery of PTX chemosensitivity in MDR cells. As expected, this newly developed intelligent drug delivery system could effectively control MDR, both in vitro and in vivo.

pH and redox dual-responsive copolymer micelles with surface charge reversal for co-delivery of all-trans-retinoic acid and paclitaxel for cancer combination chemotherapy.

BACKGROUND: Co-delivery all-trans-retinoic acid (ATRA) and paclitaxel (PTX) is an effective strategy for cancer therapy. However, in many previous reported ATRA conjugated co-delivery systems, the ATRA was released slower than PTX, and the total drug release of ATRA far lower than that of PTX. PURPOSE: We designed and prepared a pH and redox dual responsive drug delivery system (DA-ss-NPs) co-delivery ATRA and PTX for cancer therapy. The surface charge of DA-ss-NPs could change from negative to positive under tumor slightly acidic microenvironment, and both drugs could be quickly released from DA-ss-NPs under intracellular high concentration of glutathione (GSH). METHODS: The DA-ss-NPs were constructed by encapsulating PTX into the hydrophobic core of the polymer micelles, in which the polymer was synthesized by conjugating ATRA and 2,3-Dimethylmalefic anhydride (DMA) on side chains of Cystamine dihydrochloride (Cys) modified PEG-b-PAsp (named DA-ss-NPs). The surface charge of DA-ss-NPs under different pH conditions were detected. And the drug release was also measured under different concentration of GSH. The therapeutic effect of DA-ss-NPs were investigated in Human lung cancer A549 cells and A549 tumor-bearing mice. RESULTS: The zeta potential of DA-ss-NPs was -16.3 mV at pH 7.4, and which changed to 16 mV at pH 6.5. Cell uptake experiment showed that more DA-ss-NPs were internalized by A549 cells at pH 6.5 than that at pH 7.4. In addition, in presence of 10 mM GSH at pH 7.4, about 75%-85% ATRA was released from DA-ss-NPs within 48 h; but less than 20% ATRA was released without GSH. In vivo antitumor efficiency showed that the DA-ss-NPs could affectively inhibite the tumor in compared with control groups. CONCLUSION: The charge-reversal and GSH-responsive DA-ss-NPs provide an excellent platform for potential tumor therapy.