Novel Multifunctional Nanocarriers Co-delivery Of Using A Containing Polymeric Prodrug Carrier For Gastroenterology Cancer Combination Therapy

Objective:Multi-drug combination therapy with different mechanisms can overcome drug resistance and improve safety and efficacy.It is a promising cancer treatment strategy.Differences in the physicochemical properties and pharmacokinetic properties of the combination may result in undesirable uptake and biodistribution of the two drugs at the tumor site.The multifunctional nanocarrier co-loading drug is an ideal strategy to effectively avoid these limitations and improve the therapeutic effect of chemotherapy drugs.Colorectal cancer and pancreatic cancer are one of the leading causes of cancer-related death in digestive tract tumors.Chemotherapy 1s the only systemic treatment that has been shown to be effective for advanced colon and pancreatic cancer.This study aimed to explore the treatment of digestive tract tumors with new multifunctional nanocarrers combined with different chemotherapeutic drugs.Methods(1)A nanocarrier system consisting of a 5-DFUR-based prodrug polymer and a regageinib combined chemotherapy was designed by introducing a disulfide bond between 5-deoxyfluorouridine and a polymer backbone.5-deoxyfluorouridine and regorafemb have significant synergistic effects on the inhibition of cancer cell proliferation in pancreatic cancer,prostate cancer and colon cancer.Nanocarriers promote co-encapsulation of these two agents and achieve effective earier drug interactions.�(2)One of the problems faced by combination therapy in clinical transformation 1s the lack of a co-loading strategy for PPMP and chemotherapeutic agents.We have developed a polymer nanocarrier based on PPMP prodrug(POEG-b-PPPMP)to overcome this limitation.The POEG-b-PPPMP sustained release system allows the release of active PPMP over an extended period of time.More importantly,POEG-b-PPPMP can self-assemble to form micelles and achieve synergistic coding with other anticancer drugs.We systematically evaluated the size,structure,and drug loading efficiency of POEG-b-PPPMP-based nanocarriers.The antitumor activity of the drug-free POEG-b-PPPMP and doxorubicin-loaded POEG-b-PPPMP was also studied in vitro and in vivo.Results:(1)After POEG-co-PVDFUR treatment with regorafenib,cells treated with POEG-co-PVDFUR micelles were more effective in inhibiting proliferation and migration of cancer cells.The POEG-co-PVDFUR loaded with regorafenib demonstrated its superior antitumor activity.In the mouse pancreatic cancer model,the doses of 5-deoxyfluorouridine and regorafenib were 10 mg/kg,respectively,and the tumor growth inhibition rate reached 95%.(2)In vivo therapeutic experiments in mice POEG-b-PPPMP/adriamycin was most effective in inhibiting tumor growth in all treatment groups.The doxorubicin-loaded POEG-b-PPPMP micelles exhibited excellent 42-day stability at 4�C.Doxorubicin loaded in POEG-b-PPPMP micelles showed a higher level of cytotoxicity than doxorubicin loaded in the doxorubicin formulation.In the 4T1 tumor model,the order of tumor inhibition was doxorubicin/POEG-B-PPPMP>doxorubicin/POEG-B-POM?POEG-B-PPPMP>POEG-B-POM.A decrease in the accumulation of doxorubicin in the nanocarrier group in normal tissues,particularly in the heart,will help reduce doxorubicin-related toxicity and allow administration of higher doses of doxorubicin to maximize therapeutic effects.Conclusions:(1)The POEG-co-PVDFUR nano-bifunctional carrier system consists of a poly-ohgoethylene glycol methacrylate(POEG)hydrophilic block and regorafenib for 5-deoxyfluorouridine and reggae Nie's co-delivery.The POEG-co-PVDFUR micelle loaded with regorafenib inhibited tumor growth and prolonged survival more effectively in the invasive mouse pancreatic cancer model(Panc02).The micellar preparation is co-loaded with regorafenib and 5-deoxyfluorouridine.This prodrug micellar system provides a promising anticancer strategy for effective combination of tumor-targeted therapy and conventional chemotherapy.(2)The novel POEG-b-PPPMP prodrug-based micellar nanocarrier consists of 7 units of PPMP and 15 units of POEG for the effective delivery of water-insoluble anticancer drugs.POEG-b-PPPMP retains the biological role of PPMP well.Doxorubicin loaded in POEG-b-PPPMP micelles exhibited slow release kinetics in vitro and sustained tumor killing in mice.The combination of doxorubicin and POEG-b-PPPMP results in inhibition of doxorubicin-induced GCS up-regulation,increased accumulation of pro-apoptotic ceramide,and enhanced cytotoxicity against tumor cells.Systemic administration of doxorubicin formulated in POEG-b-PPPMP micelles resulted in significant inhibition of 4T1.2 tumors,which was more potent than doxorubicin and POEG-b-POM/doxorubicin.