PH/glutathione Dual-response Gene/vaccine Carrier For Cancer Therapy

With the rapid development of materials science in recent decades,nano-sized nanocarriers have been applied in various fields of biomedicine.Due to their unique properties such as size,charge,hydrophilicity,hydrophobicity,and surface properties,they were employed to solve key problems such as poor stability,low solubility,drug release burst,and high toxic and side effects of drugs or biologically active molecules.Some new types of stimili responsive systems can,depending on the physiological microenvironmental characteristics of different diseases,not only have the ability to target lesions tissue or diseased cells,but also enable controlled release of drugs,genes,or vaccines in target cells.Responsive delivery vectors can effectively increase drug availablility efficiency and reduce the side effects of drugs on normal tissues,especially for cancer therapy.Nanocarriers were utilized with charge-reversal function and redox response for gene therapy and immunotherapy of tumors.The details are as follows: 1.Microenvironment-driven cascaded responsive hybrid carbon dots as a multifunctional theranostic nanoplatform for imaging-traceable gene precise delivery.Herein,a multi-stage and cascaded responsive theranostic nanoplatform based on functionalized carbon dots for TRAIL gene precise delivery and imaging tracking was prepared by electrostatic self-assembly between pH-triggered cleavable PEGylated shell and disulfide bonds incorporated polyethyleneimine(600 Da)end-capped hyperbranched poly(amido amine)(HPAP)functionalized carbon dots core,which was synthesized by a microwave-assisted one-pot strategy of citric acid pyrolysis with HPAP as precursor for simultaneous passivation and functionalization.The cascaded responsive property endows this nanoplatform with prolonged circulation time in blood benefiting from cleavable PEGylated shielding,effective accumulation at the tumor tissue induced by elevated EPR effect resulting from microenvironment-driven synchronous charge-conversion and size-shrinkage and controlled gene release ability inside the cytosol facilitated by GSH-triggered HPAP degradability.The in vitro experimental results confirmed that such blood-tissue-cells cascaded responsive hybrid carbon dots not only possessed of considerable quantum yield(27%)for cell-imaging,but also exhibited enhanced and selective tumor cells inhibition efficiency through TRAIL-mediated apoptosis signaling pathways as well as excellent cellular and blood compatibility.In vivo results further demonstrated imaging-trackable tumor-specific accumulation ability and improved antitumor activity with low side effects.This cascaded responsive theranostic nanoplatform for imaging-traceable tumor-specific gene precise delivery not just provides a multifunctional solution,but more lies in proposing an integrated and synchronized strategy paving the way for designing new theranostic nanomedicines on the basis of precision medicine.2.Charge convertial vaccine carrier for improving cellular immunity.A charge convertable shell based on the intracellular lysosomal pH response promotes lysosomal escape of the vaccine vector,and HPAP in response to GSH increases the release rate of OVA in the HPAP/OVA complex.In this chapter,ovalbumin(OVA)was used as an immunotherapeutic antigen model.After HPAP/OVA complex was formed with positively charged HPAP,PPD and HPAP/OVA with charge reversal function was used to prepare PPD@HPAP/OVA via electrostatic interaction.As results shown that PPD@HPAP/OVA can effectively induce cellular immunity and humoral immunity.In particular,it can assist the vaccine vector to achieve lysosomal escape by using the PPD structure with charge convertion.After The HPAP/OVA complex enters the cytoplasm,HPAP was degrated rapidly by GSH.The release of OVA makes it possible to increase the efficiency of cross-presentation,inducing the formation of efficient center-memory CD8+T,and cause a higher level of cellular immunity.And through immunohistochemical analysis,with PPD@HPAP/OVA can effectively extend the time of immunization,to reduce the drug dose and improve the efficacy of tumor immunotherapy is of great help.