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WIREs Nanomed Nanobiotechnol
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Targeting cancer cells in the tumor microenvironment: opportunities and challenges in combinatorial nanomedicine

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Cancer therapies of the future will rely on synergy between drugs delivered in combination to achieve both maximum efficacy and decreased toxicity. Nanoscale drug delivery vehicles composed of highly tunable nanomaterials (‘nanocarriers’) represent the most promising approach to achieve simultaneous, cell‐selective delivery of synergistic ratios of combinations of drugs within solid tumors. Nanocarriers are currently being used to co‐encapsulate and deliver synergistic ratios of multiple anticancer drugs to target cells within solid tumors. Investigators exploit the unique environment associated with solid tumors, termed the tumor microenvironment (TME), to make ‘smart’ nanocarriers. These sophisticated nanocarriers exploit the pathological conditions in the TME, thereby creating highly targeted nanocarriers that release their drug payload in a spatially and temporally controlled manner. The translational and commercial potential of nanocarrier‐based combinatorial nanomedicines in cancer therapy is now a reality as several companies have initiated human clinical trials. WIREs Nanomed Nanobiotechnol 2016, 8:208–222. doi: 10.1002/wnan.1358 This article is categorized under: Biology-Inspired Nanomaterials > Lipid-Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Nanocarriers for combination drug delivery. The anatomical drawing in the top half of the figure shows three targeting considerations used in nanocarrier design: tissue‐, cell‐, and macromolecule‐level targeting. The bottom half of the figure depicts three novel nanocarriers designed to deliver multiple therapeutic agents to the tumor utilizing one or more of these targeting approaches. Nanocarrier (a) shows a biodegradable nanoscale liposomal polymeric gel engineered to release SB505124, a small molecule inhibitor of the TGFβ1 receptor, as well as IL‐2 within the tumor. Nanocarrier (b) depicts a particle‐within‐a‐particle encapsulation strategy, whereby dioleoyl phosphatidic acid‐coated drug cores were created out of gemcitabine monophosphate (GMP) and cisplatin. GMP and cisplatin drug cores were subsequently loaded into PLGA nanoparticles to generate dual‐loaded nanocarriers. Of the three nanocarriers depicted here, this nanocarrier is the only one that uses an active (cell‐level) targeting approach: Anisamide was attached to the outside of these nanoparticles to target sigma receptor‐overexpressing cancer cells. Nanocarrier (c) shows PLGA‐PEG/G0‐C14 nanoparticles with siRNA molecules contained in their core. A pro‐drug form of cisplatin was embedded in the polymeric nanoparticle shell.

Reproduced by permission of Mandy Root‐Thompson (© 2015).

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Biology-Inspired Nanomaterials > Lipid-Based Structures
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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