Dual Drugs Loaded In Situ Polysaccharide Hydrogels For Cancer Therapy

In current,chemotherapy is one of the main treatments for cancer patients.However,the anticancer drugs have no selectivity,they will to lead to serious side effects to both tumor cells and normal cells.To solve these problems,we develop a drug delivery system based on in situ polysaccharide hydrogels,and the injectability,degradablity,stimulus responsiveness and biocompatibility of the hydrogels are focused.At the same time,two kinds of anticancer drugs cisplatin(CDDP)and doxorubicin(DOX)which have synergistic effect are loaded into the hydrogels,and the controlled delivery behavior and anticancer effect are evaluated.The final purpose is to find an anticancer drug delivery system which is safe,nontoxic and can be used in local lesions,and prolong the release of anticancer drug.1.In this paper,the ?-PL/A-Pul/BPEI hydrogels were prepared in aqueous solution by Schiff base reaction with aldehyded pullulan(A-Pul),s-poly-L-lysine(?-PL)and branched polyethyleneimine(BPEI).The imine bonds were rapidly cross-linked into network of the hydrogel within 80 s.Scanning electronic microscopy images showed the hydrogels displayed a cross-linked structure and the average pore size were ranged from 58.8 to 81.3 ?m.Rheology test indicated the hydrogels maintained good mechanical properties.Water contact angles and swelling studies suggested the hydrogels could swell in water with max swell ratio of 1559%and had pH and temperature dependence of equilibrium swelling ratio.The hydrogels were degradable and could be injected either before or after gelation,and displayed a self-healing process in ddH2O at room temperature based on the dynamic uncoupling and recoupling of the imine bonds.2.The ?-PL/A-Pul/BPEI hydrogels were used as drug carriers,and the CDDP and DOX were cross-linked into the network of the s-PL/A-Pul/BPEI hydrogels by Schiff base reaction.The drug-loaded hydrogels had higher drug loading and encapsulation ratio and the drugs release behaviors exhibited the release of CDDP and DOX was in a controlled manner.Moreover,the drugs released faster in acidic tumor microenvironment and the released drugs retained its original inhibitory action.The MTT assays implied the hydrogels were non-cytotoxic on mice bone marrow mesenchymal stem cells and human liver cells(Huh-7).Therefore,the hydrogels have potential application as drug carriers in vivo.3.The sterilized ?-PL45/A-Pul200/BPEI2 solution was subcutaneously injected into dorsal areas of Kun Ming mice.The hydrogel was formed qulicky in vivo,and the hydrogel was kept about 6 days in vivo and displayed excellent degradability.The sterilized drugs-loaded hydrogelssolution was also injected into the tumor bearing mice,the results revealed that the drugs-loaded hydrogels had high anti-tumor efficiency.The ?-PL45/A-Pul200/BPEI2(CDDP+DOX)group had better ability in inhibiting tumor cell proliferation,indicating that CDDP and DOX had synergistic effect.In addition,the drugs-loaded hydrogels hardly had impairment for heart,liver,spleen,lung and kidney of the mice.The ?-PL45/A-Pu1200/BPEI2 hydrogels have potential application as drug carriers in vivo.