Tumor-overexpressed enzyme responsive amphiphiles small molecular self-assembly nano-prodrug for the chemo-phototherapy against non-small-cell lung cancer.

Rational design of self-assembly drug amphiphiles can provide a promising strategy for constructing nano-prodrug with high drug loading, smart stimuli-responsive drug release and high tumor selectivity. Herein, we report a small molecular amphiphile prodrug that can self-assemble into multifunctional nano-prodrug for enhanced anticancer effect by the combination of chemotherapy and phototherapy (PDT/PTT). In this prodrug, the simple insertion of quinone propionate into hydrophilic drug Irinotecan (Ir) generates suitable amphiphiles that endow a good self-assembly behavior of the prodrug and transform it into a stable and uniform nanoparticle. Interestingly, this excellent self-assembly behavior can load phototherapy agent ICG to form a multifunctional nano-prodrug, thereby enhancing the chemotherapeutic effect with PDT/PTT. Importantly, the quinone propionic acid moiety in the prodrug showed a high sensitivity to the overexpressed NAD(P)H:quinone oxidoreductase-1 (NQO1) in non-small cell lung cancer (NSCLC) cells, and this sensitivity enables the disassembly of nano-prodrug and efficient NQO1-responsive drug release. To further enhance the drug accumulation on tumor tissue and migrate the blood clearance, a biomimetic nano-prodrug has been successfully explored by coating hybrid membrane on the above nano-prodrug, which displays high selective inhibition of tumor growth and metastasis on NSCLC mice model. Our findings provide new insights into the rational design of tumor-overexpressed enzyme responsive nano-prodrug for cancer combinational therapy.

Tumor-microenvironment activated duplex genome-editing nanoprodrug for sensitized near-infrared titania phototherapy.

Near-infrared (NIR)-light-triggered nanomedicine, including photodynamic therapy (PDT) and photothermal therapy (PTT), is growing an attractive approach for cancer therapy due to its high spatiotemporal controllability and minimal invasion, but the tumor eradication is limited by the intrinsic anti-stress response of tumor cells. Herein, we fabricate a tumor-microenvironment responsive CRISPR nanoplatform based on oxygen-deficient titania (TiO2-x ) for mild NIR-phototherapy. In tumor microenvironment, the overexpressed hyaluronidase (HAase) and glutathione (GSH) can readily destroy hyaluronic acid (HA) and disulfide bond and releases the Cas9/sgRNA from TiO2-x to target the stress alleviating regulators, i.e., nuclear factor E2-related factor 2 (NRF2) and heat shock protein 90α (HSP90α), thereby reducing the stress tolerance of tumor cells. Under subsequent NIR light illumination, the TiO2-x demonstrates a higher anticancer effect both in vitro and in vivo. This strategy not only provides a promising modality to kills cancer cells in a minimal side-effects manner by interrupting anti-stress pathways but also proposes a general approach to achieve controllable gene editing in tumor region without unwanted genetic mutation in normal environments.

A self-assembled nanoplatform based on Ag2S quantum dots and tellurium nanorods for combined chemo-photothermal therapy guided by H2O2-activated near-infrared-II fluorescence imaging.

A nanoplatform based on Ag2S quantum dots (QDs) and tellurium nanorods (TeNRs) was developed for combined chemo-photothermal therapy guided by H2O2-activated near-infrared (NIR)-II fluorescence imaging. Polypeptide PC10AGRD-modified TeNRs and Ag2S QDs were co-encapsulated in 4T1 cell membrane to prepare a nanoplatform (CCM@AT). Ag2S QDs and TeNRs in the CCM@AT were used as a fluorescence probe and photosensitizer, and a chemotherapeutic prodrug and quenching agent to quench the fluorescence of Ag2S QDs, respectively. After the CCM@AT was specifically targeted to the tumor site, the TeNRs were dissolved by the high concentration of H2O2 at the tumor site to light up the fluorescence of Ag2S QDs for NIR-II fluorescence imaging. In addition, the generated toxic TeO66- molecules decreased ATP production by selective cancer chemotherapy, which is beneficial for photothermal therapy. The elevated temperature due to photothermal therapy in turn promoted the chemical reaction in chemotherapy. In vitro and in vivo toxicity results showed that the CCM@AT possesses high biocompatibility. Compared to single photothermal therapy and chemotherapy, the synergistic chemo-photothermal therapy can effectively suppress the growth of 4T1 tumor. This all-in-one nanoplatform provides a boulevard for the combination therapy of tumors guided by NIR-II fluorescence imaging. STATEMENT OF SIGNIFICANCE: NIR-II fluorescence imaging shows the characteristics of low tissue absorption, reflection, and scattering, which can greatly reduce the influence of autofluorescence in vivo. However, the non-negligible effect of autofluorescence is still observed in fluorescence imaging in vivo. Therefore, there is an urgent need to develop a strategy of controlled release of fluorescence for accurate imaging and tumor therapy. Here, Ag2S quantum dots (QDs) with NIR-II fluorescence emission and good photothermal conversion efficiency are used as a fluorescence probe and photosensitizer, and tellurium nanorods (TeNRs) are used as a chemotherapeutic prodrug and quenching agent to quench the fluorescence of Ag2S QDs. This multiple nanoplatform provides an inspiration for the combination therapy of tumor guided by NIR-II fluorescence imaging.