The Synthesis And Characterization Of Platinum-based And Genetic Nanodrugs And Their Application In Nervous Tumors

Neuroblastoma(NB)is the most common extracranial solid tumor of infancy,and also a common nervous tumor.Pertaining to the remarkable potency,platinum compounds underline the regimens of chemotherapy.Nevertheless,the undersirabkle side effect due to its non-specific toxicity to the vital organs post administration encouraged researchers to develop an alternative formulation for pursuit of improved toxicity to the tumors and reduced toxicity to the organs.Aiming for imporved therepeutic efficacy,cantharidin,a potent natural toxin demonstrating drastic anti-tumor potency in a broad array of malignancies including NB,was attempted to conjugate with hybrid platinum(IV)prodrug to create cantharidin-platinum(IV)prodrug(Can Pt).Furthermore,aiming for reduced nonspecific toxicity,the drug conjugated was proposed to encapsulate into a liposome formulation to manufacture a nano-prodrug,refered as Can Pt nanoparticle(Can Pt-NP).Subsequent investigations validated its therapeutic advanatges in treatment of NB.On the other hand,gene therapy has emerged as one of the revolutionary approaches for the management of the commonest,most malignant primary central nervous system tumor,glioblastoma(GBM).Nevertheless,the deficiency of appropriate synthetic delivery systems prohibits its treatment into practical applications.To handle this drawback,we compiled multiple chemistry-based strategies into manufacture of the gene delivery formulations to pursue improved tolerability of deoxyribonucleic acid(DNA)to the enzymatic degradation in the biological environment and its prolonged retention in the systemic circulation.Following studies substantiate that our gene delivery formulations were capable of persisting the systemic retention of DNA.In attempt for tumor therapy,we further attached ligand cyclic(Arg-Gly-Asp)peptide(c RGD)to the end of the gene delivery formulations,which was validated to prompt tumor-targeted delivery and gene expression of the loaded anti-angiogenic gene of soluble fms-like tyrosine kinase 1(s Flt1)at the targeted tumor cells,thereby exerting anti-angiogenesis of the tumors for inhibition of tumor growth.Of note,the safet y p r o f i l e o f o u r g e n e delivery formulations encouraged the utilities of gene therapy as superior treatment modality as the clinical tools.Moreover,to advocate the practical applications of gene therapy,messager ribonucleic acid(mRNA)due to its negligible possible of alter the genomic sequence of the host,was further attempted for treatment of malignant tumors.Given the vulnerability of mRNA in biological milieu,delivery vehicles are required to provide adequate protection for it.Here,mRNA was complexed with a mixture of nano-system materials to form a gene nano-vehicle.The ionic complex core of the gene nano-vehicle consisting of opposite-charged polylysine(PLys)and mRNA is crosslinked though redox-responsive disulfide linkage,thus avoiding structural disassembly for exposure of mRNA to harsh biological environments.The genomic nano-vehicle has prolonged systemic retention and improved gene expression in GBM due to a series of design strategies.According to these results,we have demonstrated the clinical potential of platinum nano-prodrug in NB,and the therapeutic benefits of genomic nano-vehicles in GBM,which portends tempting aspects in development of innovative nanomedicine for cancer management.