Microfluidic assembly of small-molecule prodrug cocktail nanoparticles with high reproducibility for synergistic combination of cancer therapy

Abstract Therapeutic nanoparticles (NPs) self-assembled from small molecular (pro)drug entities, opens up novel avenues for the generation of a wide range of drug delivery systems. Particularly, cocktail NPs created by co-assembly of multiple therapeutics often show profound efficacy beyond their individual agents. However, fabrication of synergistic NPs with high reproducibility and capability to deliver multiple therapeutics in a predefined ratio remains a challenge, which deters NP therapeutics from further clinical translation. In this work, a simple but versatile strategy has been developed to combine drug reconstitution and supramolecular nanoassembly to prodrug cocktail nanoparticle fabrication with microfluidics. Prodrugs reconstructed by PUFAylation were self-assembled into hybrid nanoparticles via microfluidic chip to synergistically deliver two chemotherapeutic drugs, 7-ethyl-10-hydroxy camptothecin (SN38) and paclitaxel (PTX), in a single nanoparticle container. In vitro cell-based assays demonstrate that the combinatorial chemotherapy is superior to each prodrug used alone while reduces the dosage of both drugs at the same time. Furthermore, the double-drug combination suppresses colon tumors by 86% at a total dosage of 16.7 mg/kg through synergy, and histological analysis indicates the safety of the hybrid nanoparticles. In general, this work shows that the nanomedicine synthesized by microfluidics provides considerable advantages including better size control and reproducibility, and great potential in effective combination therapy. It is expected to be applied to the fabrication of more chemical agent combination for other cancer types.