Abstract
Therapeutic drug synergism intervened in cancer treatments has been demonstrated to be more effective than using a single effector. However, it remains inherently challenging, with a limited cell count from tumor samples, to achieve potent personalized drug cocktails. To address the issue above, we herein present a nanodroplet cell processing platform. The platform incorporates an automatic nanodroplet dispenser with cell array ParaStamp chips, which were fabricated by a new wax stamping approach derived from laser direct writing. Such approach enables not only the on-demand de-wetting with hydrophobic wax films on substrates but also the mask-less fabrication of non-planar microstructures (i.e. no photolithography process). The ParaStamp chip was pre-occupied with anti-cancer drugs and their associate mixtures, enabling for the spatially addressable screening of optimal drug combinations simultaneously. Each droplet with a critical volume of 200 nl containing with 100 cells was utilized. Results revealed that the optimal combination reduces approximate 28-folds of conducted doses compared with single drugs. Tumor inhibition with the optimally selected drug combination was further confirmed by using PC-3 tumor-bearing mouse models. Together, the nanodroplet cell processing platform could therefore offer new opportunities to power the personalized cancer medicine at early-stage drug screening and discovery.
Highlights
Synergistic combination of two or more drugs has been a major avenue targeting cancers[1,2]
The translation from in vitro to in vivo optimal drug combinations has been successfully performed with standard multi-well plates, relatively little effort has been directed toward using cell arrays as biosensor tools for pre-clinical in vivo assays[8,11,21]
We demonstrated that the PDMS ParaStamp could be achieved with various characteristic sizes [Fig. 2(e)], in which the sizes behave in a linear relationship depending on the designed parameters for laser micromachining [Fig. 2(f)]
Summary
Synergistic combination of two or more drugs has been a major avenue targeting cancers[1,2]. Cell-based microarray platforms have been demonstrated to address the issues of critical drug volume, cell-source limitation, or high-throughput and high-content screening[12,13,14,15,16,17]. A recently developed approach involved cell microarray with cancer stem cells (CSCs) to potentially address the tumor heterogeneity in vivo[18]. To address the technology gap described above, we present the nanodroplet cell processing platform for high-throughput screenings of optimal drug combinations. We demonstrated that approximate 500-fold miniaturization does not impact the in vivo outcome (81 test spots per 22 × 22mm2; 100 cells in 200 nl per spot) Taken together, these findings highlight our newly developed nanodroplet cell processing platform could become a cost-effective, purpose-tailored and high-throughput toolkit for improving pre-clinical drug screening efficacy
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