Programmed Nanococktail Based on pH-Responsive Function Switch for Self-Synergistic Tumor-Targeting Therapy

Tumor-targeting combination chemotherapy is an important way to improve the therapeutic index and reduce the side effects as compared to traditional cancer treatments. However, one of the major challenges in surface functionalization of nanoparticle (NP) is accomplishing multiple purposes through one single ligand. Upon such consideration, methotrexate (MTX), an anticancer drug with a targeting moiety inspired by the similar structure of folate, could be used to covalently link with lipid-polymer conjugate (DSPE-PEG) via a pH-sensitive dynamic covalent imine (CHN) bond to synthesize the acid-induced function “targeting-anticancer” switching DSPE-PEG-CHN-MTX. We hypothesize that using this kind of MTX prodrug to functionalize NP’s surface would be conductive to combine the early phase active targeting function and the late-phase anticancer function in one nanosystem. Herein, a nanococktail is programmed for codelivery of epirubicin (EPI) and MTX by co-self-assembly of acid-dissociated EPI-phospholipid (PC) complex and acid-cleavable DSPE-PEG-CHN-MTX conjugate. The obtained nanococktail (MTX-PEG-EPI-PC NPs) could not only actively target folate receptors-overexpressing tumor cells but also respond to acidic endo/lysosomes for triggering the on-demand release of pharmaceutically active EPI/MTX. The intracellular drug distribution also demonstrated that the system could codeliver two drugs to individual target sites of action, inducing the significant synergistic anticancer efficiency based on different anticancer mechanisms. More importantly, the in vivo tumor accumulation and anticancer efficacy of MTX-PEG-EPI-PC NPs (via cleavable imine bond) were significantly enhanced as compared to the individual free drug, both free drugs, PEG-EPI-PC NPs, and MTX-PEG-EPI-PC NPs (via the uncleavable amide bond). This self-synergistic tumor-targeting therapy might represent a promising strategy for cancer treatment

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

“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 <i>in vivo</i> NIR fluorescence (NIRF) and photoacoustic (PA) dual-modal imaging. Both <i>in vitro</i> and <i>in vivo</i> 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