The development of the nanosized delivery systems with targeting navigation and efficient cargo release for cancer therapy has attracted great attention in recent years. Herein, a folic acid (FA) modified PEGylated polycaprolactone containing ditelluride linkage was synthesized through a facile coupling reaction. The hydrophobic doxorubicin (DOX) can be encapsulated into the polymeric micelles, and such nanoparticles (F-TeNP_DOX) exhibited redox-responsive drug release under abundant glutathione (GSH) condition due to the degradation of ditelluride bonds. In addition, flow cytometric analyses showed that the FA ligands on F-TeNP_DOX could facilitate their cellular uptake in 4T1 breast cancer cells. Therefore, F-TeNP_DOX led to the promoted drug accumulation and enhanced growth inhibition on 4T1 tumor in vivo. The obtained results suggest F-TeNP_DOX excellent potential as nanocarriers for anticancer drug delivery.

Hyaluronic acid (HA)-based nanocarriers are of great interest in the drug delivery field due to the tumor targetability via CD44-mediated recognition and endocytosis. However, sufficient tumor-specific release of encapsulated cargoes with steady controllability is necessary to optimize their outcome for cancer therapy. In this study, we constructed a light-activated nanocarrier ^TKHCENP_DOX to enable on-demand drug release at the desired site (tumor). Particularly, ^TKHCENP_DOX encapsulating doxorubicin (DOX) was self-assembled from a HA-photosensitizer conjugate (HA-TK-Ce6) containing reactive oxygen species (ROS)-sensitive thioketal (TK) linkers. Following i.v. injection, ^TKHCENP_DOX was accumulated in the MDA-MB-231 breast tumor xenograft more efficiently through preventing drug leakage in the bloodstream and the HA-mediated targeting effect. Upon internalization into tumoral cells, 660 nm laser irradiation generated ROS during a photodynamic (PDT) process to cleave the TK linker next to Ce6, resulting in light-induced ^TKHCENP_DOX dissociation and selective DOX release in the tumor area. Consequently, ^TKHCENP_DOX showed a remarkable therapeutic effect and minimized toxicity in vivo. This strategy might provide new insight for designing cancer-selective nanoplatforms with active targeting and locoregional drug release simultaneously.

Targeted T-^TKNP_VP consisting of ROS-responsive thioketal linkers realized transcranial X-PDT and X-ray-activated chemotherapy for locoregional glioblastoma treatment in vivo.

Platinum-based chemotherapy as first-line treatment for lung cancers encounters insufficient selectivity, severe side effects and drug resistance in clinics. In this study, we developed an amphiphilic prodrug of cisplatin-poly(ethylene glycol)-block-polycaprolactone and demonstrated that the prodrug formed micellar nanoparticles, NP_Pt(IV), with an average diameter of ∼100 nm. NP_Pt(IV) released platinum in response to the intracellular acidic and reductive environment, and in turn induced significant anti-proliferative activity in lung cancer cells. More importantly, NP_Pt(IV) exhibited a prominent inhibitory effect on CD133⁺ lung cancer stem cells (CSCs) and suppressed tumor growth in vivo. Unlike cisplatin treatment which eventually enriches CSCs, NP_Pt(IV) treatment prevents the accumulation of CD133⁺ lung CSCs in tumors. Therefore, NP_Pt(IV) simutaneously targeting CSCs and non-CSCs might represent a superior strategy to improve conventional anticancer therapy directed predominantly to tumor bulk populations.

With the advantages of deep tissue penetration and controllability, external X-ray-induced photodynamic therapy (X-PDT) is highly promising for combined cancer therapy. In addition to the low efficiency of photosensitizer (PS) delivery to tumor sites, however, the radiation- and drug-resistance of hypoxic cells inside the tumor after X-PDT also limit its benefits. Herein, we develop a combined therapeutic modality based on an intelligent nanosized platform (^DATAT-NP_VT) with tumor acidity-activated TAT presenting and redox-boosted release of tirapazamine (TPZ) for more precise and synchronous X-PDT and selective hypoxia-motivated chemotherapy. After ^DATAT-NP_VT has accumulated in tumor tissues via decreased blood clearance by masking of the TAT ligand, its targeting ability is reactivated by tumor pH (∼6.8), which enhances tumoral cellular uptake. Upon low-dose X-ray irradiation, the encapsulated verteporfin (VP) generates reactive oxygen species (ROS) to carry out X-PDT against MDA-MB-231 breast tumors. As a result of the abundant GSH-triggered degradation of ditelluride bridged bonds, the cascaded TPZ release and activation in the hypoxic environment following X-PDT would produce highly cytotoxic radicals to serve as antitumor agents to kill the remaining hypoxic tumor cells. This concept provides new avenues for the design of hierarchical-responsive drug delivery systems and represents a proof-of-concept combinatorial tumor treatment.