Azide-Locked Prodrug Co-Assembly into Nanoparticles with Indocyanine Green for Chemophotothermal Therapy

Abstract

Fabrication of self-delivery drug systems can surmount low drug bioavailability and achieve a precise therapeutic process. In this study, a hydrogen sulfide-responsive (H2S) small molecule prodrug was synthesized by linking two chemotherapy drugs, camptothecin (CPT) and gemcitabine (GT), using a reductive disulfide bond simultaneously with a lock GT strategy using a H2S-responsive azide group (denoted as N3-GT-CPT). The ingenious design endows the easy coprecipitation peculiarity of the prodrug with clinical indocyanine green (ICG) via a combined interaction force of hydrophobic, π–π stacking, and electrostatic interactions of anions and cations, thus producing a more stable and multifunctional therapeutic nanosystem. Considering the great photothermal and imaging ability of ICG, the obtained nanosystem showed an excellent therapeutic ability against colon tumors in vitro and in vivo with selective response to intercellular H2S, thus offering a good combination-based multiple therapy for treatment of tumors.

Implications of hydrogen sulfide in colorectal cancer: Mechanistic insights and diagnostic and therapeutic strategies

“…The synergistic ablation of colon tumors at mild apparent temperature achieved successfully performed in a mouse model using photothermal inactivation of tumor cells mediated by tumor endogenous H 2 S stimulation and drug release induced by thermal effects. To better guide and control drug release, Hou et al developed a multifunctional therapeutic nanosystem using a small molecule prodrug N 3 -GT-CPT designed to link two chemotherapeutic drugs, CPT and gemcitabine (GT), to easily co-precipitate with the photothermal agent indocyanine green (ICG) [ 243 ]. The N 3 -GT-CPT/ICG nanosystem showed selective H 2 S-triggered drug release behavior by a lock GT strategy using a H 2 S-responsive azide group.…”

Advance Progress in Assembly Mechanisms of Carrier-Free Nanodrugs for Cancer Treatment

“…Idealized prodrugs can be activated by specific stimuli in the tumor microenvironment (TME), such as acidity, high glutathione (GSH) or reactive oxygen species (ROS), and specific enzymes, for drug release on demand [81,82]. Therefore, rational design of prodrugs combined with nanotechnology for constructing carrier-free nanodrugs can significantly improve drug stability and pharmacokinetics, reduce renal clearance or degradation, extend drug circulation time, and enhance tumor accumulation via EPR effect and therapeutic efficacy [83][84][85].…”

“…Taking advantage of the redox gradient between tumor and normal cells, some specific chemical linkages can be utilized to design prodrugs which provide a prerequisite for constructing redox-responsive carrier-free nanodrugs [99]. Inspired by the chemical properties and functional effect, disulfide bonds are widely used as reductionsensitive linkers in the design of antitumor prodrugs [85,100].…”

Site-Specific Antimicrobial Activity of a Dual-Responsive Ciprofloxacin Prodrug

“…Another reductant found in a large number of bacterial species is hydrogen sulfide (H 2 S), , which has been linked to increased bacterial survival in the oxidative microenvironment created by the host immune system. − This process results in high concentrations of H 2 S in the infection microenvironment, which could be used in targeted drug delivery strategies. One of the more selective reactions of H 2 S is its reduction of azides to amines, a reaction that has been widely used in many prodrugs, responsive drug delivery systems, and fluorescent probes. − …”