Abstract
Targeted delivery of drugs to tumor cells, which circumvent resistance mechanisms and induce cell killing, is a lingering challenge that requires innovative solutions. Here, we provide two bioengineered strategies in which nanotechnology is blended with cancer medicine to preferentially target distinct mechanisms of drug resistance. In the first ‘case study’, we demonstrate the use of lipid–drug conjugates that target molecular signaling pathways, which result from taxane-induced drug tolerance via cell surface lipid raft accumulations. Through a small molecule drug screen, we identify a kinase inhibitor that optimally destroys drug tolerant cancer cells and conjugate it to a rationally-chosen lipid scaffold, which enhances anticancer efficacy in vitro and in vivo. In the second ‘case study’, we address resistance mechanisms that can occur through exocytosis of nanomedicines. Using adenocarcinoma HeLa and MCF-7 cells, we describe the use of gold nanorod and nanoporous vehicles integrated with an optical antenna for on-demand, photoactivation at ~650 nm enabling release of payloads into cells including cytotoxic anthracyclines. Together, these provide two approaches, which exploit engineering strategies capable of circumventing distinct resistance barriers and induce killing by multimodal, including nanophotonic mechanisms.
Highlights
Despite the risks associated with cytotoxic cancer chemo-therapies, such as taxanes and anthracyclines, they remain a key part of treatment for more than half a century [1]
We previously reported that drug tolerant cancer cells (DTCCs) express a high concentration of plasma membrane lipid rafts compared to drug naïve cancer cells (DNCCs) [6]
We determined that phosphatidylcholine (PC) and cholesterol resulted in significantly increased uptake into DTCCs vs. drug naïve parental cancer cells (DNCCs) and, to a lesser degree, phosphatidic acid (PA) at levels higher than the other lipids tested (Figure 1D)
Summary
Despite the risks associated with cytotoxic cancer chemo-therapies, such as taxanes and anthracyclines, they remain a key part of treatment for more than half a century [1]. Decorating nanoparticles with aptamers, antibodies, proteins, and small peptides, such as arginylglycylaspartic acid (RGD), have shown improvement in reaching tumor cells and avoiding some of the toxicity associated with the cytotoxic payloads [3] Resistance mechanisms such as endosomal recycling and molecular biological signals that rely on cell survival pathways can limit the efficacy of these approaches [4]. Emerging approaches including plasmonics may provide novel opportunities to release drug payloads in a manner that potentially circumvents resistance via endosomal recycling [9] Harnessing these discoveries to improve the uptake of anticancer drugs into subpopulations of refractory cells, circumvent molecular and physical barriers to treatment response to enhance cell killing is a critical milestone in drug development
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