Methotrexate–Camptothecin Prodrug Nanoassemblies as a Versatile Nanoplatform for Biomodal Imaging-Guided Self-Active Targeted and Synergistic Chemotherapy

Abstract

"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.

Simple surface functionalization of magnetic nanoparticles with methotrexate‐conjugated bovine serum albumin as a biocompatible drug delivery vehicle

“…In addition, as the concentrations of Fe 3 O 4 @BSA‐MTX NPs and pure MTX were increased, their inhibitory effects on tumor cells were significantly increased compared to control group . MTX as a folic acid analog can bind tightly to the dihydrofolate reductase enzyme and lead to disruption of folic acid metabolism and interruption of DNA and RNA synthesis . Therefore, the delivery of sufficient doses of MTX can cause significant toxicity in tumor cells .…”

“…[41] MTX as a folic acid analog can bind tightly to the dihydrofolate reductase enzyme and lead to disruption of folic acid metabolism and interruption of DNA and RNA synthesis. [42] Therefore, the delivery of sufficient doses of MTX can…”

Recent Advances in Targeted Tumor Chemotherapy Based on Smart Nanomedicines

“…FA analogs due to the high structural similarity with FA can also be exploited as a tumor‐targeted ligand to recognize FR. For instance, methotrexate (MTX, Food and Drug Administration (FDA)‐approved antimetabolite drug) has been demonstrated with the tumor‐targeting capacity . Li et al have recently reported the targeted delivery of MTX–camptothecin (CPT) prodrug, in which MTX was conducive to FA–receptor‐mediated endocytosis of prodrug .…”

“…For instance, methotrexate (MTX, Food and Drug Administration (FDA)‐approved antimetabolite drug) has been demonstrated with the tumor‐targeting capacity . Li et al have recently reported the targeted delivery of MTX–camptothecin (CPT) prodrug, in which MTX was conducive to FA–receptor‐mediated endocytosis of prodrug . In the meanwhile, combination chemotherapy, in vivo near‐infrared (NIR) fluorescence, and photoacoustic dual‐modal imaging are concurrently achieved due to codelivered CPT and MTX and NIR cyanine dye.…”

A Reduction‐responsive Amphiphilic Methotrexate‐Podophyllotoxin Conjugate for Targeted Chemotherapy

“…The cytotoxicity of MTX-CC-PPT at 72 hw as thought to result from cleavage of carbonic ester owing to the presence of esterasei n tumor cells. [15] Furthermore, cells incubatedw ith free PPT showedt he highest cytotoxicity.I mportantly,o ur prodrug NAs showeda no bviousd ecrease in PPT toxicitya nd provided a controlled drug-releasep rocess. In addition, after the cells were incubatedw ith MTX-SS-PPT NAs and MTX-CC-PPT NAs for 6h,aCalcein-AM/PI Double StainingK it was applied to stain live cells (green)a nd dead cells (red;F igureS16,E SI).…”