A NEW 'SMART' POLYELECTROLYTE DRUG CARRIER RESPONSIVE TO PH AND GLUTATHIONE FOR INTRACELLULAR DELIVERY OF ANTISENSE

摘要

Cytoplasmic delivery of enzyme-susceptible biomolccular drugs is one of the major limitations in many therapeutic strategies, such as gene and antisensc therapy, and vaccine development. Development of better delivery systems that can enhance the endosomal escape of such biothcrapcutics and thereby avoid degradation by lysosomal enzymes, is still a major goal of drug delivery scientists. Inspired by the action of pH-sensitive peptides in (he protein coats of certain viruses to enable endosomal escape of their DNA or RNA cargoes [1], we have been designing, synthesizing and characterizing a family of novel pH-rcsponsive polymers that can similarly enhance cytoplasmic delivery of enzyme-susceptible drugs such as DNA, RNA, antisense oligonucleotidcs (asODNs), proteins and peptides. [2-6] In this study, a novel functionalized monomer, pyridyl disulfidc acrylatc (PDSA), was synthesized and incorporated into an amphiphilic copolymer consisting of methncrylic acid and butyl acrylatc, which resulted in a pH-sensitivc, membrane-disruptive torpolymor with functional groups, that allow thiol-containing molecules to be readily conjugated. We conjugated a thiol-terminaled asODN to the backbone via disulfidc linkages. We also conjugated a cysleinc-hexalysinc peptidc to the backbone via disulfide linkages, and then used the hexalysine groups to ionically-complex an asODN to the backbone.