Design And Application Of Cationic Peptide Vectors In Small Molecule Drugs And Gene Delivery

Tumor is one of the major diseases that seriously threaten the human health.Currently,chemotherapy is one of the major methods for tumor therapy.However,the efficacy of most of the traditional anti-tumor drugs is limited by poor selectivity,toxic side effects,multidrug resistance and other shortcomings.In this regard,macromolecular drugs(eg,proteins or genes)are of great interest anticancer drugs because of their unparalleled potency and specificity.However,intracellular delivery of these macromolecules is a huge challenge.Therefore,the development of a new type of anti-tumor drugs with high selectivity,new mechanism of action and target of action,has become an urgent problem to be solved.In this regard,the drug delivery system(DDS)has been explored to address the dilemma faced by these drugs.Over the past few decades,many biomaterials have been extensivelyused in a variety of fields,includingthe medicine,biology,chemistry and tissue engineering.To date,one of the specific areas in which these biomaterials have had a significant impact is cancer treatment.Cationic polypeptides represented by cell penetrating peptides(CPPs)are highly concerned due to their unique mechanisms of action and their promising prospects for drug delivery.In this paper,we designed a series of cationic peptide vectors based on the cell penetrating peptide TAT and antimicrobial peptide CAMEL for CPT and gene delivery..1.Antitumor activity of TAT-CPT conjugates.CPT was attached to TAT for two aims: hydrophilic TAT improve the water solubility and stability of CPT by conjugation;hydrophobic CPT enhance the cell penetrating activity of TAT,and therefore more CPT molecules can be delivered into cancer cells.In this study,we designed and synthesized a series of TAT-CPT conjugates for exploring the sites in TAT for introduction of CPT and the mode of conjugation for TAT and CPT.Our results showed that the increased hydrophobicity of TAT by conjugation with CPT could significantly improve the cell penetrating activity of TAT.As a result,TAT-CPT conjugates can deliver more CPT molecules into tumor cells,and showedsignificantly increased antitumor activity compared with CPT molecule.In addition,we also confirmed that the ester bond as linker for TAT-CPT conjugates was more stable than the disulfide bond.2.Study on SP7 as Gene Delivery Vector.CAMEL is a hybrid antimicrobial peptide against Gram-positive and Gram-negative bacteria.Studies have shown that CAMEL can penetrate cells and induce cell death by acting on mitochondria,indicating that CAMEL has the potential as a drug delivery carrier.SP,a neuropeptide containing 11 amino acids,can rapidly internalize by specific binding to tachykinin-1(NK-1)receptors.NK1 receptors are highly expressed in many types of cancers,such as breast cancer,astrocytoma and glioblastoma.Thus,in this study,we constructed a tumor-targeted chimeric peptide SP7 by linking CAMEL to SP.Meanwhile,we also attached the octadecanoic acid to the N-terminus of SP7 to improve its transfection efficiency.The results showed that the plasmid delivery ability of CAMEL and SP7 were remarkably increasedafter conjugation with octadecanoic acid;Compared with CAMEL,the cell penetrating activity and transfection ability of stearylated SP7 exhibits significant selectivity to the cells highly expressing NK1 receptors.