Rational Design And Anticancer Activities Of Cancer-target PLGA Nanocarriers

Due to the efficient biodegradability, biocompatibility and negligible toxicity,the PLGA becomes hot research into into several decades. In this study, different types of targeted nano-medicines were produced by using PLGA polymer as nano-carrier and the anticancer activity was carried out in vitro assessment. The main results are as follows:1. Water-soluble vitamin E(TPGS) has been widely used as an emulsifier, solubilizing agent and surfacedecoration. In this study, RGD-targeted PLGA nanoparticles(PSeD@PCTR) were designed and synthesized. Cell experiments showed TPGS could synergistically enhance the growth inhibitory effect of PSeD on Siha cells. The selective intracellular uptake and cytotoxic effect of PSeD@PCTR was found associated with RGD receptor-mediated endocytosis. Moreover, in vitro released experiments showed that the nanoparticles were a solid sphere in simulated blood environment(PBS, pH 7.4). In the pH 5.3 and lysozyme(simulation lysosomes environment), nanoparticles presented divergent fluffy and released of PSeD. In Siha cell lysate(simulated In vivo environment), the nanoparticles were degradated completely and the released drug reached to 90%. The results showed that integrin targeting, biological response to the release of bifunctional nanoparticles provides a theoretical basis for targeted drug in clinical application.2. This study constructed double targeting nanoparticles by ACPP and AE105 surface decoration to achieve selective cellular uptake and enhanced anticancer efficacy. Moreover, panels of human cancer cell lines were found to be susceptible to Au-1a@NPs/ACPP/AE105, with an IC50 of 0.03 μM. From the cellular uptake experiments demonstated that Au-1a@NPs/ACPP/AE105 nanoparticles are absorbed in MDA-MB-231 cells by the tumor microenvironment and uPAR mediated. Study on molecular mechanism showed: Au-1a@NPs/ACPP/AE105 entered the cell, inhibited the TRxR activity and stimulated ROS generation. Furthermore, Au-1a@NPs/ACPP/AE105 stimulated FAK activation, stimulated Ras/MEK/ERK and PI3K/Akt pathways, leading to the activation or overexpression of MMPs and uPA. The results demonstrated that Au-1a@NPs/ACPP/AE105 inhibited the invasion, migration and proliferation.3. Resistance of cancer to radiotherapy and/or chemotherapy is one of the reasons of treatment failure and recurrence. Wherein the treatment of melanoma apt to radiotherapy and chemotherapy tolerance, which is an important factor leading to the low cure rate. Gold Star nanoparticles have a unique nature of radiotherapy and hyperthermia, the near-infrared laser irradiation could instantaneously generate heat, and widely used as a good radiation sensitizer. Therefore, multi-amino PEI and gold star were used to prepare folate targeted Au@PLGA-PEI-BSeC-FA nanoparticles. Herein, our results demonstrated that the Au@PLGA-PEI-BSeC-FA under X-ray and near infrared stimulation played as a fatal factor to inhibit A375 cells growth. After the X-ray and near-infrared irradiate, ROS levels and anti-tumor activity was positively correlated. In summary, hyperthermia could promote radiotherapy, and then synergy with chemotherapy drugs inhibited proliferation of cancer cells to achieve efficient killing cancer cell and low toxicity towards normal cell. Both hyperthermia, radiotherapy, chemotherapy of Au@PLGA-PEI-BSeC-FA nanoparticles may provides a new direction to improve the treatment of melanoma.In summary, the new targeted nano-drugs may have potential applications in cancer treatment.