Application Of Novel Self-assembled Microspheres In Cancer Immunotherapy

Cancer immunotherapy has become a promising strategy to reduce the growth,metastasis and recurrence of tumors by activating a patient’s immune system.The past two decades have witnessed great advances in cancer immunotherapy.Personalized cancer vaccines based on patient-specific neoepitope or nucleic acid emerged in the year of 2017.Monoclonal antibodies targeting programmed cell death-1(PD-1)or cytotoxic T-lymphocyte-associated antigen 4(CTLA-4)have been commercialized and used in clinic to treat several types of tumors.However,the therapeutic effect of cancer immunotherapy is limited,because it is difficult for drug to reach tumor site instead of being distributed in other tissues of the patients.So doctors need to use high dose of drug to achieve the therapeutic effect of tumor.Moreover,this may be partly due to the presence of some immunosuppressive enzymes in the tumor,such as IDO,which can inhibit the activity of T cells and lead the immune escape of tumor cells.Drug delivery systems(DDSs)have attracted much attention for the treatment of cancer and other diseases.DDSs can significantly alter the drug pharmacokinetics,associated sided effects.The advantages of applying DDSs was to the immunotherapy including: 1)changing the pharmacokinetics of drugs in order to stabilize drug molecules;2)enhancing the stability of drugs in the blood circulation the preventing them from being degraded and inactivated by enzymes;3)enhancing the biological distribution of drugs in specific tumor sites and improving the bioavailability of drugs;4)controlling the drug release within the tumor site.These characteristics can improve the treatment of cancer immunotherapy and reduce adverse reactions.In this study,we applied hydrogen bonding interactions among single macromolecules to construct self-assembling uniform microspheres for the codelivery of anti-PD1 and 1-MT to synergistically enhance cancer immunotherapy.The main works are as follows:(1)Using ultrasonic method,amphiphilic polymer with multi-armed poly(ethylene glycol)(PEG)containing with ureidopyrimidone(Upy)moiety can directly crosslink to each other through their complementary non-covalent interactions in water.The self-assembled microspheres were shown to load anti-PD1 antibodies efficiently by directly mixing them in aqueous solution.(2)We prepared ureidopyrimidone(Upy)-modified 1-methyl-D-trytpphan(U-MT)which can be connected to the microspheres via UPy-mediated quadruple array of hydrogen bonds.This microsphere based delivery platform(1a-PMM)can load anti-PD1 and 1-MT at the same time.(3)In vitro experiments showed that the drug-loaded microspheres(1a-PMM)have good biocompatibility and also can inhibit the activity of indole-2,3 dioxygenase.Under physiological conditions,drugs can be released at different release rate.The rapid of IDO inhibitors might alleviate immunosuppression and improve the efficacy of follow-up checkpoint blocker-based therapy.(4)In vivo experiments showed that the microspheres(1a-PMM)can significantly improve the retention of PD-1 antibody.Using the mouse model of MC-38 and B16F10 tumor models,we demonstrated that synergistic delivery of anti-PD1 and 1-MT enhanced the immune function of effector T cells and reduced immunosuppression in the tumor microenvironment,thus producing an effective anti-tumor effect.No weight loss or damage to healthy organs were observed during the treatment,indicating that1a-PMM microspheres had good biocompatibility.