pH-Responsive Assembly of Gold Nanoparticles and “Spatiotemporally Concerted” Drug Release for Synergistic Cancer Therapy

Abstract

A challenge in using plasmonic nanostructure-drug conjugates for thermo-chemo combination cancer therapy lies in the huge size discrepancy; the size difference can critically differentiate their biodistributions and hamper the synergistic effect. Properly tuning the plasmonic wavelength for photothermal therapy typically results in the nanostructure size reaching ∼100 nm. We report a new combination cancer therapy platform that consists of relatively small 10 nm pH-responsive spherical gold nanoparticles and conjugated doxorubicins. They are designed to form aggregates in mild acidic environment such as in a tumor. The aggregates serve as a photothermal agent that can selectively exploit external light by their collective plasmon modes. Simultaneously, the conjugated doxorubicins are released. The spatiotemporal concertion is confirmed at the subcellular, cellular, and organ levels. Both agents colocalize in the cell nuclei. The conjugates accumulate in cancer cells by the rapid phagocytic actions and effective blockage of exocytosis by the increased aggregate size. They also effectively accumulate in tumors up to 17 times over the control because of the enhanced permeation and retention. The conjugates exhibit a synergistic effect enhanced by nearly an order of magnitude in cellular level. The synergistic effect is demonstrated by the remarkable reductions in both the therapeutically effective drug dosage and the photothermal laser threshold. Using an animal model, effective tumor growth suppression is demonstrated. The conjugates induce apoptosis to tumors without any noticeable damage to other organs. The synergistic effect in vivo is confirmed by qRT-PCR analysis over the thermal stress and drug-induced growth arrest.

Spatiotemporally and Sequentially-Controlled Drug Release from Polymer Gatekeeper–Hollow Silica Nanoparticles

“…The primary strategy to overcome MDR is co-administration of multiple drugs789. However, varying drug uptake and suboptimal drug concentrations in heterogeneous tumour environments limit the synergistic efficacy of administered drugs101112.…”

Mechanisms of cooperation in cancer nanomedicine: towards systems nanotechnology

“…Rapidly diffusing imaging agents are able to anchor in tumors by binding to previously injected gold nanoparticles that have had time to accumulate there due to the EPR effect [29]. Similarly, small (10 nm) gold nanoparticles engineered to release conjugated doxorubicin in acidic tumor environments, can subsequently self-assemble to form larger gold aggregates that are then used for photothermal therapy [28, 87]. In vitro experiments show how nanoparticles that self-assemble in response to enzymatic activity may be able to perform logic computations towards the diagnosis of tumor state [88].…”

Update on current and potential nanoparticle cancer therapies

“…Additional work has focused on enhancing the penetration, retention, and release of therapeutic cargo of nanoparticle-based therapeutics in cancer cells by taking advantage of the relatively low pH and increased protease expression in the tumor microenvironment. For instance, matrix metalloproteinase 2 sensitive molecules [40], pH-sensitive linkers [41], and ester linkages [42] have been utilized to improve uptake and drug delivery to tumor cells.…”