| Compared with systemic drug administration,local drug delivery can significantly increase the concentration and utilization of the drugs at the site of administration,and reduce the side effects of drugs to other sites.In classical local drug delivery systems,drugs are directly encapsulated in carrier materials or implants with a relatively single performance,which is difficult to effectively meet the treatment needs of diseases with complex pathological characteristics or strict drug delivery requirements.Nanoparticles with diverse structures and adjustable properties have been widely used in the field of drug delivery.However,there are also problems such as low drug delivery efficiency and insufficient drug enrichment at the target site after systemic drug delivery.The nanocomposite local drug delivery system prepared by combining the local drug delivery system with nanoparticles is expected to combine the advantages of these two systems and achieve more efficient drug delivery in complex disease models.Based on this,according to the physiological characteristics and drug delivery requirements of cancer and diabetes,we constructed composite hydrogels and microneedle drug delivery platforms with nanoparticles.These two nanocomposite local drug delivery systems could respond to the physiological microenvironment and improve the treatment efficacy of diseases by enhancing tumor tissue penetration and intelligently controlling drug release.The specific research content is as follows:1)A nanoparticle-hydrogel drug delivery system responsive to tumor acidic microenvironment was constructed to solve the problem of the poor drug penetration in tumor tissue.This drug-loaded hydrogel(namely PDO gel)formed by in-situ chemical cross-linking is composed of oxaliplatin(OXA)conjugated G5 polyamidoamine(G5-OXA)and oxidized dextran(Dex-CHO),able to degrade and release small size G5-OXA(～ 6.8 nm)in vivo.Our study has found that the released G5-OXA could passively diffuse in the tumor utilizing its small size,and actively penetrate into the tumor through transcytosis,thereby enhancing the penetration and retention of the drug in the tumor.In the orthotopic 4T1 tumor model on the immunodeficient mouse,the PDO gel has been confirmed to effectively inhibit 67% of tumor growth and 76% of lung metastases.In addition,PDO gel could also improve the immune microenvironment of tumor tissues in the 4T1 model of immunologically sound mice utilizing the effect of immunogenic cell death of tumor cells induced by OXA,and improved the anti-tumor immunotherapy efficacy.2)The ideal treatment for diabetes aims to mimic pancreatic functions and release insulin in response to changes in blood glucose levels(BGLs).To address this drug delivery requirement,a microneedle(MN)patch loaded with fast pH-responsive nanoparticles(SNPs)was constructed to achieve insulin release with changes in glucose concentration.After encapsulating insulin in SNPs(SNP(I)),more than 90% of insulin was released within 4 h at high glucose levels,while only about 30% was released at low glucose levels.The SNP(I)and pH-insensitive nanoparticles loaded with glucose oxidase(GOx)and catalase(CAT)(iSNP(G+C))were co-encapsulated into the MN patch and fixed to the skin using transdermal drug delivery technology.With the increase of BGLs,GOx catalyzes the glucose to produce an acidic microenvironment,which triggers the rapid release of insulin loaded in SNPs to achieve the timely control of blood glucose.In vivo experiments have shown that this nanocomposite MN patch loaded with SNP(I)had a fast glucose-responsive property and could maintain BGLs within normal ranges for up to 8 h. |
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