Abstract 1721: Hypoxia penetrating ultra-small nanoparticle for anti-cancer effect in Glioblastoma

Abstract

Abstract Glioblastoma multiforme (GBM) is a lethal brain tumor currently without successful treatment options. Chemotherapeutic agents are the frontline in the management of GBM. Nonetheless, accessibility of the brain tumor is greatly impeded by the poor blood-brain barrier (BBB) penetration of drugs, which needs immediate attention. Ultra-small multifunctional nanoparticle offers a great promise in overcoming the delivery barriers to GBM. The primary goal of our research is to develop BBB targeted nanoparticle that can selectively deliver drugs to GBM and trigger cell death. We developed Anti-GBM drug, such as temozolomide (TMZ) encapsulated biocompatible, ultra-small nanoparticle using Lactoferrin (LAC) protein. Further, we chemically conjugated LAC with tumor hypoxia biomarker homing molecule, Acetazolamide (ATZ) to obtain LAC-ATZ nanoparticle. To validate our hypothesis of hypoxia targeting, we evaluated the carbonic anhydrase-IX (CAIX) receptor expression in human brain tumor section. The IHC data demonstrated significant overexpression of CAIX in tumor tissue compared to healthy human brain tissue section. Literatures have reported overexpression of LRP-1 in endothelial blood vessel of GBM tumor. Thus, use of LAC-ATZ will enhance its penetration across the BBB and delivery of TMZ in hypoxic core of GBM. To achieve the effective BBB penetration, we engineered LAC-ATZ@TMZ nanoparticle that demonstrated homogenous ultra-small particle size of average diameter of 20-30 nm using TEM analysis. The SDS-PAGE analysis demonstrated the conjugation of LAC with ATZ. Our preliminary data in GBM cells, U87MG suggested the dose dependent cell uptake of DiD-fluorescence labeled LAC-ATZ nanoparticle. The nanoparticles are selective in targeting the U87MG cell when compared to healthy microglial BV2 cells. Thus, it is supporting the potential of LAC-ATZ nanoparticle for targeting the GBM tumor with limited effect in healthy brain tissue. We developed conditioned BBB cell culture model to demonstrate the penetration of LAC-ATZ across the BBB. Based on the exciting preliminary outcome in this study builds a strong rational of using LAC-ATZ nanoparticle for overcoming the bottle neck barrier of BBB with improved anti-GBM response. Keywords: Glioblastoma multiforme (GBM), blood-brain barrier (BBB), Lactoferrin (LAC), Acetazolamide (ATZ) Citation Format: Mohd A. Rauf, Katyayani Tatiparti, Samaresh Sau, Arun K. Iyer. Hypoxia penetrating ultra-small nanoparticle for anti-cancer effect in Glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1721.