A precision-guided MWNT mediated reawakening the sunk synergy in RAS for anti-angiogenesis lung cancer therapy.

Abstract

Multi-walled carbon nanotube (MWNT) with its versatility has exhibited tremendous superiority in drug delivery. Despite plenty of researches on MWNT based delivery systems, precision-guided assistances to maximize their profitable properties are still lacking in substantive progress. We developed here a dual-targeting and co-delivery system based on MWNT for antiangiogenesis therapy in lung cancer which aimed at renin-angiotensin system (RAS) dysregulation by synergistically conducting angiotensin II type 1 receptor (AT₁R) and type 2 receptor (AT₂R) pathway. In this work, iRGD peptide connected to polyethyleneimine (PEI) was linked to MWNT skeleton, accompanying with candesartan (CD) conjugated to MWNT mediated by cystamine (SS). The functionalized MWNT is assembled with plasmid AT₂ (pAT₂) to form iRGD-PEI-MWNT-SS-CD/pAT₂ complexes. iRGD and CD act as pilots for complexes to dually target symbolic ανβ3-integrin and AT₁R both overexpressed on tumor angiogenic endothelium and lung cancer cell. CD as chemotherapy showed synergistic downregulation of VEGF when combining of pAT₂ and efficiently inhibited angiogenesis. iRGD-PEI-MWNT-SS-CD/pAT₂ complexes greatly appreciated drug activities by changing drug distribution and exhibited remarkable tumor growth suppression in A549 xenograft nude mice. Our work presents that such dual-targeting strategy highly improves the delivery performance of MWNT and open a new avenue for RAS related lung cancer therapy.