In Situ Drug Controlled Release Formulation Based On Enzyme Responsive Hydrogel And Its Performance Study

Recent advances on hydrogel research indicated that hydrogel-based drug delivery systems have great potential on treating chronic diseases and tumors that require continuous treatment.Drug delivery formulation based on the injectable hydrogel can be implanted into the body,and the drug is restricted in the hydrogel that can effectively increase the drug release cycle,thereby improved the bioavailability and therapeutic effect of the drug.When hydrogel was used as a drug controlled release carrier,since the clinical drugs are mostly hydrophobic small molecule compounds,they are difficult to be uniformly dispersed in the hydrogel and then released at a desired rate.At present,the preparation of nanoparticles with water-soluble and stable dispersion of water-insoluble drugs by nanotechnology is the best method to solve this problem.Both rheumatoid arthritis(RA)and triple-negative breast cancer(TNBC)are diseases that seriously interfere with human health.In the clinical treatment of RA,it is difficult to find a long-term solution.As the disease worsens,doctors can only increase the dose or use the new drug,but the subsequent side effects of drug are more serious.These will put a heavy burden on the patient.TNBC is one of the most prone to recurrence and metastasis in breast cancer.In the treatment of TNBC,people focus on cutting off the chance of recurrence and metastasis after surgery,reducing burden of life and mental of patients.Therefore,in order to prevent the recurrence of TNBC,we designed an in-situ forming injectable MMP responsive hydrogel for encapsulation of sunitinib nanoparticles,combined with anti-angiogenic therapy and high expression of metalloproteinase(MMP)in TNBC tumors.The drug-loaded MMP responsive hydrogel was implanted in the incision after tumor surgery.The drug-loaded MMP responsive hydrogel was responsive to release sunitinib to achieve the purpose of cutting off the recurrence of TNBC.Further,in order to solve the problem that the RA drug Iguratimod(IGUR)has a large gastrointestinal injury and it is difficult to maintain effective treatment for a long time,we designed an in-situ forming injectable hydrogel for encapsulation of iguratimod nanoparticles(NanoIGUR).IGUR was released in the body for a long time to treat RA after the NanoIGUR-loaded hydrogel was subcutaneous injected.The specific contents are as follows:(1)In-situ forming injectable MMP responsive hydrogel for encapsulation of nanosunitinib and controlled release of therapeutics of inhibited triple-negative breast cancer recurrence.Sunitinib was first encapsulated in the polylactic acid-polyethylene glycol-polylactic acid(PDLLA-PEG-PDLLA)micelles by liquid antisolvent precipitation technology,and then loaded into hydrogel that was cross-linked by HS-MMP-SH that was a thiolated crosslinker with matrix metalloproteinase response.In vitro,the biological effects of NanoSUN-loaded MMP hydrogel on human breast cancer cells MDA-MB-231 and vascular endothelial cells HUVEC were evaluated.In vivo,the efficacy of NanoSUN-loaded MMP hydrogel in preventing postoperative recurrence in MDA-MB-231 breast cancer mice was evaluated.(2)In-situ forming injectable hydrogel for encapsulation of nanoiguratimod and sustained release of therapeutics of rheumatoid arthritis.Iguratimod was first encapsulated in polyvinyl alcohol micelle by liquid antisolvent precipitation technology,and then loaded into hydrogel that was cross-linked by HS-PEG-SH that was a thiolated crosslinker.In vitro,the biological effects of NanoIGUR-loaded hydrogel on fibroblast-like synoviocytes from rheumatoid arthritis(RA-FLS)were evaluated.In vivo,the pharmacokinetics of NanoIGUR-loaded hydrogel was assessed and the efficacy of NanoIGUR-loaded hydrogel in treating collagen-induced arthritis(CIA)rats was evaluated.