Combined Anti-prostate Tumor Study Of Adriamycin And Immunomodulatory Molecule JQ1 Encapsulated In Polydopamine Nanomaterials

Prostate cancer is the most common new cancer worldwide and its cause remains unclear,but its incidence has increased significantly in recent years.The pathogenesis of prostate cancer is also complex and various factors,such as age,obesity,family history of prostate cancer and certain genetic mutations appear to be associated with prostate cancer.For men with clinically limited or below moderate risk prostate cancer,active surveillance or treatment in the form of surgery or radiation therapy are the recommended treatment options.In contrast,for locally advanced or metastatic prostate cancer,androgen deprivation therapy(ADT)via chemical castration or orchiectomy combined with anti-androgen therapy is the current common treatment.However,most prostate cancers can develop into destructive resistant prostate cancer(CRPC).Because of the aggressive nature of prostate cancer cells,they become progressively resistant to different treatments and can stimulate pro-tumor signaling pathways,leading to insensitivity to chemotherapy,radiation,immunotherapy and ADT,which in turn exacerbates the disease.In contrast,the short circulation time,low bioavailability and resistance of conventional chemotherapy,which affects normal cell proliferation,as well as the side effects specific to chemotherapy(cardiac,hepatic,renal and bone marrow toxicity,etc.),seriously affect the quality of life of patients.Clinically,two or more modalities are often used in combination to improve cure rates.Combining immunotherapy with drug therapy has become a hot topic in solid tumor research in recent years.Adriamycin(doxorubicin,DOX)is one of the chemotherapeutic agents commonly used in the treatment of prostate cancer,but DOX lacks specificity for tumor cells,is prone to serious systemic toxicities and has severe cardiotoxicity.Adriamycin increases the release of tumor antigens and regulates the function of CD8+T cells by inducing apoptosis of tumor cells,but PD-L1 expression is enhanced in tumor tissues treated with chemotherapeutic agents such as adriamycin.JQ1,a member of the BET family,can effectively inhibit PD-L1 expression on tumor cells and activate T cells,thereby overcoming immune tolerance.The immunomodulatory small molecule JQ1 significantly reduces the expression of PD-L1 on tumor cells,associated dendritic cells,and macrophages,thereby enhancing the viability of anti-tumor cytotoxic T cells.In addition,JQ1 inhibits the inflammatory response of macrophages and attenuates the systemic inflammatory process without abrogating the antitumor immune response.The combination of the chemotherapeutic drug DOX and the immunomodulatory small molecule JQ1 is expected to enhance the sensitivity of tumors to immune checkpoint therapy and can work together to enhance the body’s own immunity and thus effectively kill tumor cells.Nanocarrier drugs are a novel way to treat tumors,which have been widely recognized by the medical community for their ability to effectively load drugs with good sustained release properties using nanomaterials as carriers,thus showing high efficacy and safety.Polydopamine(PDA)is an oxidized polymer of dopamine,which is produced by autopolymerization reaction due to oxidation under specific temperature and acid-base conditions.PDA is simple to synthesize,easy to modify,has almost negligible cytotoxicity and can effectively alleviate inflammatory responses.These properties of PDA make it suitable for widespread use as an in vitro and in vivo biocarrier in biomedical fields(e.g.drug delivery).Based on the above analysis,we believe that the synthesized polydopamine nanoparticles loaded with the chemotherapeutic drug DOX and the immunomodulatory small molecule JQ1 for the treatment of prostate cancer can reduce the toxic side effects of DOX and produce good synergistic therapeutic effects.Objective:To investigate the composite materials constructed from polydopamine nanoparticles loaded with adriamycin and JQ1,including their drug retarding ability,growth inhibitory effect on human prostate cancer PC-3 cells,and reduction of PD-L1 expression in tumors,to provide a theoretical basis for clinical improvement of the antitumor effects of chemotherapeutic drugs and possible improvement of adverse effects.Methods:Under specific acid-base and temperature conditions,we obtained PDA nanoparticles by self-polymerization by magnetic stirring of dopamine hydrochloride solution overnight and observed their structures using transmission electron microscopy.At suitable temperature and pH conditions,we loaded adriamycin and JQ1 on the surface of these particles.The nanodrugs were incubated in environments with different levels of acidity and alkalinity,and the release of DOX was measured at different time periods using UV spectrophotometer.Subsequently,human prostate cancer PC-3 cells were treated with nanoparticles of different drug loading concentrations,respectively,and their effects on cell proliferation activity were examined by cell counting method-8(CCK-8)and flow cytometry.Finally,protein blotting analysis was used to assess the protein expression of PD-L1 in PC-3 cells treated with nanomedicine.Results:We successfully synthesized a novel PDA nanoparticle,which can be loaded with DOX and JQ1,and these particles not only have good pH sensitivity,but also can significantly enhance the anti-tumor activity of the drug.The immunomodulatory small molecule JQ1 and DOX co-transport carrier can not only solve the low water solubility of JQ1 but also reduce the toxic side effects of adriamycin,which can produce a good synergistic anti-tumor effect.