Increased Gold Nanoparticle Retention in Brain Tumors by in Situ Enzyme-Induced Aggregation

Abstract

The treatment of brain tumors remains a challenge due to the limited accumulation of drugs and nanoparticles. Here, we triggered the aggregation of gold nanoparticles (AuNPs) using legumain to enhance the retention of chemotherapeutics in brain tumors. This nanoplatform, AuNPs-A&C, is comprised of Ala-Ala-Asn-Cys-Lys modified AuNPs (AuNPs-AK) and 2-cyano-6-aminobenzothiazole modified AuNPs (AuNPs-CABT). AuNPs-AK could be hydrolyzed to expose the 1,2-thiolamino groups on AuNPs-AK in the presence of legumain, which occurs by a click cycloaddition with the contiguous cyano group on AuNPs-CABT, resulting in formation of AuNPs aggregates. This strategy led to an enhanced retention of the AuNPs in glioma cells both in vitro and in vivo due to the blocking of nanoparticle exocytosis and minimizing nanoparticle backflow to the bloodstream. After conjugation of doxorubicin (DOX) via a pH-sensitive linker to AuNPs-A&C, the efficiency for treating glioma was improved. The median survival time for the DOX-linked AuNPs-A&C increased to 288% in comparison to the saline group. We further show the use of the AuNPs-A&C for optical imaging applications. In conclusion, we provide a strategy to increase nanoparticle tumor accumulation with the potential to improve therapeutic outcome.

Progress in tumor-associated macrophage (TAM)-targeted therapeutics

“…The proteolytic activity of legumain specific to the Ala-Ala-Asn substrate sequence has been used in the design of pro-drugs or smart drug delivery systems that target both TAMs and cancer cells [200][203][204]. Although many drug delivery systems targeting transferrin receptor have been reported, to our knowledge, all these systems are tailored toward targeting cancer cells expressing the receptor or enhancing transcytosis across blood brain barrier, and neither the effect on nor the application to affect TAMs has been reported [205][206][207].…”

Tumor Microenvironment‐Responsive Dual Drug Dimer‐Loaded PEGylated Bilirubin Nanoparticles for Improved Drug Delivery and Enhanced Immune‐Chemotherapy of Breast Cancer

“…Mountains of NDDSs rely on the enhanced permeability and retention (EPR) effect to passively target tumor tissue . Nevertheless, their tumor accumulations remain low and need improvement.…”

A feasible strategy for self-assembly of gold nanoparticlesviadithiol-PEG for photothermal therapy of cancers

“…Among various documented methods to construct assembled GNPs, interparticle crosslinking is one of the most effective strategies, 17,18 which can be readily performed by simple chemical synthesis to construct stable assembled GNPs. These linkers efficiently shorten the distance between GNPs and keep the assemblies stable in aqueous solutions.…”