(205b) Dual-Targeted Heteromultivalent Liposomal Gene Delivery for Cancer Therapy

The broad success of cancer chemotherapy is hindered by nonspecific delivery which causes harmful side effects and limits drug dosages.  Nanoparticles functionalized with cancer-targeting ligands have shown promise in directing drug delivery, but are still limited by off-tumor binding to healthy tissues that express low levels of the molecular target.  Dual-targeted heteromultivalent nanoparticles overcome this limitation by requiring overexpression of two separate targets for localization; by simultaneously targeting two unique cancer biomarkers, off-tumor binding can be avoided. Dual-targeted heteromultivalent liposomes were synthesized using two biomarker-binding peptides; one specific to the α₅β₁ integrin and one specific to the α₆β₄ integrin.  In a multivariate study, heteromultivalent liposomes with varying peptide valencies, peptide ratios, and peptide binding affinities were delivered to cells with different integrin concentrations.  Binding and internalization of fluorescent liposomes were then evaluated to understand the effect of valency and dual-targeting on binding kinetics and delivery.  The optimal formulation was used as a gene delivery vehicle to achieve improved delivery, specificity and therapy against cancer.  The insights gained from this study inform rational design of modular heteromultivalent nanoparticles for enhanced specificity to target tissue and for the creation of more effective cancer treatments.