Drug-eluting microarrays to identify effective chemotherapeutic combinations targeting patient-derived cancer stem cells

Abstract

A new paradigm in oncology establishes a spectrum of tumorigenic potential across the heterogeneous phenotypes within a tumor. The cancer stem cell hypothesis postulates that a minute fraction of cells within a tumor, termed cancer stem cells (CSCs), have a tumor-initiating capacity that propels tumor growth. An application of this discovery is to target this critical cell population using chemotherapy; however, the process of isolating these cells is arduous, and the rarity of CSCs makes it difficult to test potential drug candidates in a robust fashion, particularly for individual patients. To address the challenge of screening drug libraries on patient-derived populations of rare cells, such as CSCs, we have developed a drug-eluting microarray, a miniaturized platform onto which a minimal quantity of cells can adhere and be exposed to unique treatment conditions. Hundreds of drug-loaded polymer islands acting as drug depots colocalized with adherent cells are surrounded by a nonfouling background, creating isolated culture environments on a solid substrate. Significant results can be obtained by testing <6% of the cells required for a typical 96-well plate. Reliability was demonstrated by an average coefficient of variation of 14% between all of the microarrays and 13% between identical conditions within a single microarray. Using the drug-eluting array, colorectal CSCs isolated from two patients exhibited unique responses to drug combinations when cultured on the drug-eluting microarray, highlighting the potential as a prognostic tool to identify personalized chemotherapeutic regimens targeting CSCs.personalized medicine | chemopredictive | cancer stem cell | microarray | combination therapy

A cell-based microarray to investigate combinatorial effects of microparticle-encapsulated adjuvants on dendritic cell activation

“…69 Thus, technologies that aim to reduce compounds and cells required for screening greatly expedite identification of leads. Polymeric, particle-based approaches encapsulating adjuvants can provide delivery to DCs via phagocytosis and controlled release.…”

MSN‐on‐a‐Chip: Cell‐Based Screenings Made Possible on a Small‐Molecule Microarray of Native Natural Products

“…The first cell‐compatible SMM was reported by Stockwell and co‐workers in the form of a polymer‐based load‐and‐release system (Figure A); by using biodegradable poly‐ dl ‐lactide/glycolide copolymer to impregnate micrometer‐size discs on a glass slide with small‐molecule compounds, followed by successful cell growth, the authors carried out image‐based cell screens and successfully identified active small‐molecule compounds that were initially trapped in the polymer but slowly diffused into nearby cells, leading to phenotypic changes. A similar approach was reported by Keselowsky et al., who used poly(ethylene‐co‐vinyl acetate) to encapsulate small‐molecule drugs . Despite being compatible with HT cell‐based screens, these polymer‐based SMM systems have some major limitations, including uncontrollable compound diffusion and a lack of long‐term storage capability .…”

Combinatorial drug delivery approaches for immunomodulation

“…Combinatorial strategies to modulate multiple immune axes in coordination are seen as an attractive strategy to overcome these barriers, the growth of which is well documented [4,9–11]. Combinatorial immunotherapy success is represented by recent clinical trials involving simultaneous administration of nivolumab and ipilimumab [12,13].…”