A Nanoliposome-based Photoactivable Drug Delivery System For Enhanced Cancer Therapy And Overcoming Treatment Resistance

Chemotherapy is the main mean for treating tumor in the clinic,but chemotherapy has weak selectivity in cancer cell,meanwhile,it is likely to develop drug-resistance,so it can not achieve treatment purpose of tumor therapy.In order to improve therapy effect of anti-tumor chemotherapy drug,we selected the common nanocarrier long circulation liposomes as drug carrier in this research,we take advantage of binary drug loading liposome,DOX was set as a drug model,based on the application of photosensitizer and activated by a specific wavelength of light and resulted in generating a lot of reactive oxygen species,we developed photo-activated nanoliposomes(PNLs)drug delivery system for overcoming drug resistance and enhancing cancer therapy.This drug delivery was investigated of safety and treatment effect systematically.The main research content contained the following sections:1.Preparation method and characterization of PNLs.The PNLs were synthesized by film dispersion method,the PNLs consist of a nanoliposome doped with anti-tumor drug doxorubicin(DOX)and photosensitizer hematoporphyrin monomethyl ether(HMME).PNLs were stable under the physiology condition,the size of the PNLs is ~126.6 nm and PNLs showed a uniform dispersed spherical form.The encapsulation efficiency of DOX was ~58.8%,the encapsulation efficiency of HMME was ~43.7%.Studies show that PNLs can generate ROS after 532 nm laser irradiation for 15 min.Besides,the release rate of anti-tumor drug was below 10%,but after the laser irradiation for 15 min,the release rate of DOX were reached about ~92.4% at8 h,the release rate of HMME were reached about ~51.6% at 8 h.2.In vitro anti-tumor activity of PNLs.in this section,we have applied human breast cancer cell MCF-7/MDR model for cytological study.cytotoxicity test revealed that Blank liposome showed high safety as drug delivery and little toxicity toward MCF-7MDR.Cellular uptake test revealed that PNLs could enter into the cytosol after4 h of incubation,DOX could enter into the cell nucleus for producing anti-tumoreffect with 532 nm laser irradiation.At the same time,PNLs with laser irradiation could generate reactive oxygen species and inhibit the expression of P-gp and reduce drug expel from MCF-7MDR,it can induce more cell apoptosis when anti-tumor drug interact with cell nucleus.Combination photodynamic therapy(PDT)and chemotherapy was able to strengthen the effect of anti-tumor and decrease multidrug resistance and reveal the distinct inhibition to MCF-7/MDR.3.In vivo anti-tumor activity of PNLs.The MCF-7/MDR tumor bearing nude mice were applied to detect tissue distribution,tumor inhibition and vivo biosafety of PNLs.According to the result of the study,PNLs could effectively prolonged the blood circulation time of liposome to make more DOX reach tumor site,on the one hand,PNLs with laser irradiation can produce ROS and release anti-tumor drug,on the other hand,it can also decrease the expression of transport protein and reduce DOX expel from MCF-7/MDR for overcoming drug resistance,the drug delivery system strengthened therapy effect of tumor by combining photodynamic therapy and chemotherapy.In addition,the release of DOX from PNLs was very slow in normal tissue,PNLs drug delivery system decreased side effects and improved the therapeutic window of DOX.In conclusion,we have successfully developed a drug delivery system which has abilities of overcoming drug resistance and enhancing tumor therapy and controlling drug release in this research,this study provides a new idea and reference to explore the novel anti-tumor drug delivery system.