NaYF4:Yb,Er upconversion nanoparticles (UCNPs) capped with long-chain carboxylic acid were synthesized and then conjugated with chitosan (CS) in the aid of N-hydroxysuccinimide. The resultant nanocompound was integrated with doxorubicin (DOX) and Roussin’s black salt (RBS), a photosensitive nitric oxide (NO) donor to produce stimuli-responsive UCNPs(DOX)@CS-RBS nanospheres as nanocarriers for controllable drug delivery. On the one hand, the encapsulated UCNPs can efficiently absorb NIR photons and convert them into visible photons to trigger NO release. On the other hand, the entrapped DOX can be released at lowered pH from the swollen nanospheres caused by stretched oleoyl-CS chains under acidic conditions. The UCNPs(DOX)@CS-RBS nanospheres exhibit great therapeutic efficacy, which is attributable to the combination of NO and DOX releases based on NO dose-dependent mechanisms. This study highlights the controllable release of NO and DOX from the same nanocarriers and the synergistic therapeutic effect on tumors, which could give new insights into improving cancer nanotherapeutics.Statement of SignificanceIn this paper, core-shell structured UCNPs(DOX)@CS-RBS nanospheres have been designed and synthesized via a step-by-step procedure. The stimuli-responsive UCNPs(DOX)@CS-RBS nanospheres act as nanocarriers for controllable drug delivery towards cancer therapy. The encapsulated UCNPs can efficiently absorb NIR photons and convert them into visible light to trigger NO release. Meanwhile, the entrapped DOX can be released from the swollen nanospheres caused by stretched oleoyl-CS chains at lowered pH typical of intracellular environment. Synergistic cancer therapy will be achieved through the combination of NO and DOX releases based on NO dose-dependent mechanisms. This study provides new drug nanocarriers with high antitumor efficacy for synergistic cancer therapy.Download high-res image (132KB)Download full-size image

CuS nanoparticles capped with a long-chain carboxylic acid were synthesized and conjugated with chitosan (CS) via N-hydroxysuccinimide. The anticancer drug doxorubicin (DOX) was then encapsulated by hydrophobic interaction, producing pH-responsive CuS(DOX)@CS nanospheres with photothermal conversion properties for controllable drug release and photothermal ablation (PTA). On the one hand, the encapsulated CuS nanoparticles can absorb NIR photons and be heated efficiently. On the other hand, the entrapped DOX can be released from the swollen CuS(DOX)@CS nanospheres caused by stretched oleoyl-CS chains at lowered pH. Combining chemotherapy and PTA, the biocompatible CuS(DOX)@CS nanospheres can provide synergistic cancer treatment, as evidenced by both in vitro and in vivo experiments. This study gives new insights into developing multifunctional drug delivery agents for cancer nanotherapeutics.

A newly designed drug–drug assembly prodrug for tumor therapy is reported. Hydrophilic irinotecan (Ir) and hydrophobic doxorubicin (DOX) were assembled into amphiphilic micelles via specific H-bond-instructing double disulfide bonding that is pH- and redox-responsive. The micelles aggregated to form water-dispersible Ir–DOX small molecule assembly (SMA) nanoparticles with an average diameter of 68.7 nm. The Ir–DOX SMA nanoparticles can release Ir and DOX simultaneously under conditions characteristic of the environment in cancer cells. Decomposition of the Ir–DOX SMA nanoparticles which gives rise to the drug release can be monitored in real time based on fluorescence resonance energy transfer (FRET) between the Ir and DOX moieties. In vitro cell experiments indicate that the Ir–DOX SMA nanoparticles are able to kill cancer cells efficiently with reduced multiple drug resistance (MDR) effect. Compared with the drug formulations such as Ir, DOX and Ir/DOX mixture, the drugs released from the Ir–DOX SMA nanoparticles can escape rapidly from the intracellular endolysosomal system and reach the nucleus, bypassing the drug efflux pump. This work provides a new concept of preparing drug delivery vehicles that may be applied in cancer chemotherapy.