Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 9, Issue 40, Pages 34650-34665Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.7b10027
Keywords
self-assembly; small molecular nanodru; self-targeted drug delivery; combination cancer therapy; real-time monitoring and imaging
Funding
- National Natural Science Foundation of China [31771029]
- Natural Science Foundation of Fujian Province of China [2016J01406]
- Jiangsu Province [BL2013015]
- Science and Technology Plan Guidance Project of Xiamen City [3502Z20159001]
- China Postdoctoral Science Foundation [2016M602074, 2017T100472]
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All-in-one carrier-free-based nano-multi-drug self-delivery system could combine triple advantages of small molecules, nanoscale characteristics, and synergistic combination therapy together. Researches have showed that dual-acting small-molecular methotrexate (MTX) could target and kill the folate-receptor-overexpressing cancer cells. Inspired by this mechanism, a novel collaborative early-phase tumor-selective targeting and late-phase synergistic anticancer approach was developed for the self-assembly of chemotherapeutic drug drug conjugate, which showed various advantages of more simplicity, efficiency, and flexibility over the conventional approach based only on single or combination cancer chemotherapy. MTX and 10-hydroxyl camptothecin (CPT) were chosen to conjugate through ester linkage. Because of the amphiphilicity and ionicity, MTX-CPT conjugates as molecular building blocks could self-assemble into MTX-CPT nanoparticles (MTX-CPT NPs) in aqueous solution, thus notably improving the aqueous solubility of CPT and the membrane permeability of MTX. The MTX-CPT NPs with a precise drug-to-drug ratio showed pH-/esterase-responsive drug release, sequential function Targeting-Anticancer switch, and real-time monitoring fluorescence Off-On switch. By doping with a lipophilic near-infrared (NIR) cyanine dye (e.g., 1 '-dioctadecyl-3,3,3 ',3 '-tetramethylindotricarbocyanine iodide, DiR), the prepared DiR-loaded MTX-CPT NPs acted as an effective probe for in vivo NIR fluorescence (NIRF) and photoacoustic (PA) dual-modal imaging. Both in vitro and in vivo studies demonstrated that MTX-CPT NPs could specifically codeliver multidrug to different sites of action with distinct anticancer mechanisms to kill folate-receptor-overexpressing tumor cells in a synergistic way. This novel, simple, and highly convergent self-targeting nanomulti-drug codelivery system exhibited great potential in cancer therapy.
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