The Synthesis And Research Of PH-sensitive And Non-pH-sensitive Nanocarriers For Cancer Therapy

Cancer is one of the most threats to human health and considered as the second underlying cause of mortality in the world.Chemotherapy is the most effective systemic treatment.However,a series of undesirable properties of conventional antitumor drugs restrict their application in clinics such as low drug bioavailability and poor water solubility.Taxol is one of the most widely used chemotherapeutic agents.Despite its excellent antitumor activity,the therapeutic efficacy of taxol is compromised by its poor solubility and the absence of selective cytotoxicity.Herein,to overcome these limitations,a novel nanoparticle drug delivery system was developed for delivery of taxol.Although nanotechnology has only just emerged at the end of the last century,it has been widely used in biomedical fields.Compared with traditional drug delivery systems,nanoparticles drug delivery systems have greater potential in many fields,such as extend blood circulation time and achieve controlled drug release.Due to the active metabolism of tumor cells,the microenvironment of tumor tissue is highly acidic compared to normal tissues.PH-triggered nanoparticle is one of the most common stimuli-sensitive nanoparticles drug delivery systems and it has been widely applied in drug transport and controlled release.It can reduce the toxicity of chemotherapeutics and enhance the antitumor effect by accumulating in tumor sites via EPR effect and selectively releasing the drug in the tumor.A novel nanoparticle drug delivery system based on Dextran-PEG-PLA copolymer was developed.Acetalated Dextran-PEG-PLA(ADPP NPs)was synthesized to obtain a pH-sensitive system.And in order to get direct comparisons of drug delivery efficacy in pH and non-pH-sensitive system,Propionic Anhydride modified Dextran-PEG-PLA(PDPP NPs)were developed as a non-pH-sensitive system.Both of them could self-assemble into stable nanoparticles in the aqueous phase.Then a hydrophobic antitumor drug,taxol,was loaded into these systems.Based on this,ADPP-taxol and PDPP-taxol Nanoparticles with high drug loading rate and stability were developed.Then the stimuli release behaviors were tested to compare the efficacy of drug release in different acidic environment.ADPP-taxol NPs were highly sensitive to acidic environment.It should be attributed to the decreased of hydrophobicity of the core resulted from the cleavage of acetal bond.The result suggest that ADPP NPs could effectively hinder the release of the encapsulated drug in normal physiological condition,while can accelerate the drug release in response to intracellular lower pH value.Finally,cytotoxicity of the two systems were assessed in vitro and in vivo compared with Taxol at the same time,and the safety of these NPs also were evaluated.The result demonstrated that both of them have good biocompatibility and biodegradability,ensured the antitumor efficacy and significantly attenuating the adverse effects of taxol.These properties make the pH-Sensitive nanoparticle drug delivery system(ADPP NPs)have tremendous potential candidate for cancer chemotherapy.