Stimuli-responsive Nanoparticles For Tumor Imaging And Therapy

In recent years,nano-drug delivery systems and nanocarriers show great promise in drug delivery and tumor imaging and diagnosis due to their small particle size,large specific surface area,good drug loading capacity,high stability and the ability to enrichment in the tumor sites.However,there are some inevitable obstacles in its application and development of nano-systems,For example,how to realize the"OFF-ON"mode to accurately detect signals in tumor sites in the process of tumor imaging,how to achieve time-targeted and site-directed release of nanomedicine in tumor sites to improve the bioavailability of nanomedicine and improve the efficiency of tumor therapy,based on the characteristics of tumor microenvironment,rational design of stimuli-responsive nanocarriers can effectively solve the above-mentioned problems.There are many kinds of stimulus based on the tumor microenvironment,which mainly include PH,redox,enzymatic stimulus response.Therefore,the stimuli-responsive nanoparticles can achieve accurate and rapid response at the target site of the tumor to rapidly release the drug or achieve other functions such as imaging diagnosis.In this work,we designed and synthesized redox-responsive nanoparticles based on tumor microenvironment and then studied their application in the diagnosis and treatment of tumors,which included the following two parts:（1）Since the concentration of glutathione（GSH）in tumor cells is nearly several thousand times than that outside tumor cells,which provides a precondition for the design of redox-responsive nanoparticles.mPEG-PADEE copolymers were synthesized by reversible addition-fragmentation chain transfer（RAFT）polymeri-zation method,during which 2-（（2,4-dinitro-N-（ethyl）phenyl）sulfonamide）ethyl methacrylate（ADEE）and poly（ethylene glycol）methyl ether methacrylate（mPEGMA）were used as the copolymer monomers.The mPEG-PADEE polymer assembly into nanoparticles in the buffer and then encapsulated the photosensitizer pheophorbide a（PhA）,forming redox-responsive nanoparticles（mPEG-PADEE/PhA）.The redox responsiveness of mPEG-PADEE nanoparticles was evaluated by ¹H NMR,UV,DLS and GPC.The sulfonamide bond on the hydrophobic segment of ADEE was cleaved under pH 7.4 and simulated intracellular GSH concentration（10 mM）,during which secondary amino groups are recovered and completely protonate,leading to micelles disassembly and rapid release of PhA.Research on HepG2 cells found that mPEG-PADEE not only could inhibit the antioxidant capacity of cells,but also could carry the PhA to the tumor sites,which could make a synergetic antitumor effect and improve the bioavailability of PhA and photodynamic therapy efficiency.（2）In this work,the redox-responsive PEDF copolymers were synthesized from2-（（2,4-dinitro-N-（3,3,3-trifluoropropyl）phenyl）sulfonamido）ethyl methacrylate（ADF）and poly（ethylene glycol）methyl ether methacrylate（mPEGMA）through RAFT polymerization.The redox responsiveness of PEDF nanoparticles was evaluated by ¹H NMR,UV and DLS.The sulfonamide bond on the hydrophobic segment of ADF was cleaved under pH 7.4 and simulated intracellular GSH concentration（10 mM）,during which secondary amino groups are recovered and completely protonate,leading to micelles disassembly and exposure of trifluoromethyl and then and reappearance of the ¹⁹F NMR signals.Cell research showed that the PEDF nanoprobes had good biocompatibility and low cytotoxicity,imaging experiments in vivo confirmed that upon thiol treatment,these nanoprobes containing ¹⁹F element showed a highly responsive“OFF-ON”¹⁹F MRI signal switch.Consequently,the amino-based smart ¹⁹F MRI probes are expected to be a starting point for the development of more exciting hydrophilic probes for in vivo ¹⁹F MRI application.