Biodistribution of TAT or QLPVM coupled to receptor targeted liposomes for delivery of anticancer therapeutics to brain in vitro and in vivo

Combination therapy has emerged as an efficient way to deliver chemotherapeutics for treatment of glioblastoma. It provides collaborative approach of targeting cancer cells by acting via multiple mechanisms, thereby reducing drug resistance. However, the presence of impermeable blood brain barrier (BBB) restricts the delivery of chemotherapeutic drugs into the brain. To overcome this limitation, we designed a dual functionalized liposomes by modifying their surface with transferrin (Tf) and a cell penetrating peptide (CPP) for receptor and adsorptive mediated transcytosis, respectively. In this study, we used two different CPPs (based on physicochemical properties) and investigated the influence of insertion of CPP to Tf-liposomes on biocompatibility, cellular uptake, and transport across the BBB both in vitro and in vivo. The biodistribution profile of Tf-CPP liposomes showed more than 10 and 2.7 fold increase in doxorubicin and erlotinib accumulation in mice brain, respectively as compared to free drugs with no signs of toxicity. Blood brain barrier prevents the delivery of chemotherapeutics into brain. To overcome this issue, we designed a doxorubicin and erlotinib loaded dual functionalized liposomal delivery system, surface modified with transferrin (Tf) and a cell penetrating peptide to enhance their translocation across the BBB into glioblastoma tumor in brain via receptor mediated transcytosis and enhanced cell penetration, both in vitro and in vivo. Our results demonstrated several fold increase in the concentration of anticancer drugs across the co-culture endothelial barrier as well as in mice brain. Thus, we believe that this study would have high impact for treating patients with glioblastoma. [Display omitted]