Design Of Drug Delivery System Based On PH And Enzyme For Tumor Therapy

Achieving precise recognition of tumor tissue is a key challenge in drug delivery.The complex tumor microenvironment has its unique composition different from normal physiological tissues,which provides space for tumor growth,but also attributes to a breakthrough for the design of drug delivery system.Based on the characteristics of tumor microenvironment,the main purpose of this thesis is to enhance the ability of targeting tumor for the designed drug delivery system.As a result,two kinds of drug delivery system were designed,which can promote tumor therapy efficiency.The designed nanomaterials were verified from three direction,namely the characterization of material properties,in vitro experiments and in vivo experiments.The detailed contents and main results are described as follows:1.A Chimeric Peptide Logic Gate Based on p H / MMP-2 Dual-stimulus Response for Precise Tumor Phototherapy.Dual stimuli-triggered chimeric peptides against the tumor microenvironment were developed for logic-gated tumor recognition for photodynamic therapy.Chimeric peptides were obtained by solid-phase peptide synthesis,which could self-assemble into spherical nanoparticles under the effect of hydrophilicity and hydrophobicity.In vitro studies showed that the negatively charged chimeric peptides were sensitive to two typical tumor markers,namely the slightly acidic tumor microenvironment and plentiful matrix metalloproteinase 2(MMP-2).Cell experiments displayed that in a rich culture environment of p H 6.5 and MMP-2,SCC-7 cells showed more absorption of chimeric peptide nanoparticles,and the difference between p H6.5 and p H7.4 reached 50% in toxicity with a Pp IX concentration of 0.8 mg/L after irradiation,and only about 25% of tumor cells survived at p H 6.5.Apparently,the presence of both slightly acidity and MMP-2 significantly enhanced the damage efficacy of nanomaterials.Therefore,chimeric peptides could undergo charge inversion from negative to positive in tumors,thereby accelerating cellular uptake.Specifically,only in the presence of both acidity and MMP-2,the enhanced cellular uptake of the chimeric peptide could be effectively activated,which could contribute to a highly specific tumor treatment in vivo and in vitro.This chimeric peptide based on "AND" logic gate would show great potential in precise tumor treatment in the future.2.A Strategy of Metal-organic Framework Delivery Based on p H/Thrombin Stilumus Triggered Enhanced Tumor ChemotherapyCutting off oxygen and nutrient supply by thrombin to limit tumor growth has been considered an attractive strategy in synergistic cancer treatment.However,the in vivo application of thrombin-based cancer treatment is limited by the delivery efficiency of thrombin.In this work,by encapsulating thrombin and prodrug tirazamine(TPZ)into acid-responsive metal-organic framework(MOF)ZIF-8 nanoparticles,a kind of biocompatible nanomaterials named as CTTZ was developed for slightly acidic and thrombin activated cancer chemotherapy,which could targeted degrade and selectively release drugs.In vitro experiments showed that CTTZ was responsive to slightly acid stimulation of the tumor microenvironment.Animal experiments displayed that CTTZ would release thrombin to block blood vessels when it was stimulated by the acid stimulus after reaching tumor cells.TPZ acted on tumor cells resulting in inhibiting tumor growth,improving the cancer chemotherapy efficiency and reducing systemic toxicity.This packaging and delivery through the MOF platform enhanced the drug's tumor targeting in an acid degradation-enzyme activated response manner,and achieved a more effective and safer way to inhibit tumor growth.Taking advantage of the tumor microenvironment's stimulus,this strategy combined with the application of MOF platform in oncology shows broad prospects and provides new ideas for the choice of carriers for the design of drug delivery system.