A Near-Infrared Light-Activated Photocage Based on a Ruthenium Complex for Cancer Phototherapy.

Conventional photocages only respond to short wavelength light, which is a significant obstacle to developing efficient phototherapy in vivo. The development of photocages activated by near-infrared (NIR) light at wavelengths from 700 to 950 nm is important for in vivo studies but remains challenging. Herein, we describe the synthesis of a photocage based on a ruthenium (Ru) complex with NIR light-triggered photocleavage reaction. The commercial anticancer drug, tetrahydrocurcumin (THC), was coordinated to the RuII center to create the Ru-based photocage that is readily responsive to NIR light at 760 nm. The photocage inherited the anticancer properties of THC. As a proof-of-concept, we further engineered a self-assembled photocage-based nanoparticle system with amphiphilic block copolymers. Upon exposure to NIR light at 760 nm, the Ru complex-based photocages were released from the polymeric nanoparticles and efficiently inhibited tumor proliferation in vivo.

Biodegradable Ru-Containing Polycarbonate Micelles for Photoinduced Anticancer Multitherapeutic Agent Delivery and Phototherapy Enhancement.

The lack of selectivity between tumor and healthy cells, along with inefficient reactive oxygen species production in solid tumors, are two major impediments to the development of anticancer Ru complexes. The development of photoinduced combination therapy based on biodegradable polymers that can be light activated in the "therapeutic window" would be beneficial for enhancing the therapeutic efficacy of Ru complexes. Herein, a biodegradable Ru-containing polymer (poly(DCARu)) is developed, in which two different therapeutics (the drug and the Ru complex) are rationally integrated and then conjugated to a diblock copolymer (MPEG-b-PMCC) containing hydrophilic poly(ethylene glycol) and cyano-functionalized polycarbonate with good degradability and biocompatibility. The polymer self-assembles into micelles with high drug loading capacity, which can be efficiently internalized into tumor cells. Red light induces the generation of singlet oxygen and the release of anticancer drug-Ru complex conjugates from poly(DCARu) micelles, hence inhibiting tumor cell growth. Furthermore, the phototherapy of polymer micelles demonstrates remarkable inhibition of tumor growth in vivo. Meanwhile, polymer micelles exhibit good biocompatibility with blood and healthy tissues, which opens up opportunities for multitherapeutic agent delivery and enhanced phototherapy.

Activating Iterative Revolutions of the Cancer-Immunity Cycle in Hypoxic Tumors with a Smart Nano-Regulator.

The activation of sequential events in the cancer-immunity cycle (CIC) is crucial for achieving effective antitumor immunity. However, formidable challenges, such as innate and adaptive immune resistance, along with the off-target adverse effects of nonselective immunomodulators, persist. In this study, a tumor-selective nano-regulator named PNBJQ has been presented, focusing on targeting two nonredundant immune nodes: inducing immunogenic cancer cell death and abrogating immune resistance to fully activate endogenous tumor immunity. PNBJQ is obtained by encapsulating the immunomodulating agent JQ1 within a self-assembling system formed by linking a Type-I photosensitizer to polyethylene glycol through a hypoxia-sensitive azo bond. Benefiting from the Type-I photosensitive mechanism, PNBJQ triggers the immunogenic cell death of hypoxic tumors under near-infrared (NIR) light irradiation. This process resolves innate immune resistance by stimulating sufficient cytotoxic T-lymphocytes. Simultaneously, PNBJQ smartly responds to the hypoxic tumor microenvironment for precise drug delivery, adeptly addressing adaptive immune resistance by using JQ1 to downregulate programmed death ligand 1 (PD-L1) and sustaining the response of cytotoxic T lymphocytes. The activatable synergic photoimmunotherapy promotes an immune-promoting tumor microenvironment by activating an iterative revolution of the CIC, which remarkably eradicates established hypoxic tumors and suppresses distal lesions under low light dose irradiation.

Photothermal "nano-dot" reactivate "immune-hot" for tumor treatment via reprogramming cancer cells metabolism.

Cancer immunotherapy, despite its enormous application prospect, is trapped in the abnormal lactic acid metabolism of tumor cells that usually causes an immunosuppressive tumor microenvironment (ITM). Inducing immunogenic cell death (ICD) not only sensitizes cancer cells to carcer immunity, but also leads to a great increase in tumor-specific antigens. It improves tumor condition from "immune-cold" to "immune-hot". Herein, a near-infrared photothermal agent NR840 was developed and encapsulated into tumor-targeted polymer DSPE-PEG-cRGD and carried lactate oxidase (LOX) by electrostatic interaction, forming self-assembling "nano-dot" PLNR840 with high loading capacity for synergistic antitumor photo-immunotherapy. In this strategy, PLNR840 was swallowed by cancer cells, then dye NR840 was excited at 808 nm to generate heat inducing tumor cell necrosis, which further caused ICD. LOX could serve as a catalyst, reducing lactic acid efflux via regulation of cell metabolism. More importantly, the consumption of intratumoral lactic acid could substantially reverse ITM, including promoting the polarization of tumor-associated macrophages from M2 to M1 type, inhibiting the viability of regulatory T cells for sensitizing photothermal therapy (PTT). After the combination of αPD-L1 (programmed cell death protein ligand 1), PLNR840 restored CD8+ T-cell activity that thoroughly cleaned the pulmonary metastasis of breast cancer in 4T1 mouse model and cured hepatocellular carcinoma in Hepa1-6 mouse model. This study provided an effective PTT strategy to boost "immune-hot" and reprogrammed tumor metabolism for antitumor immunotherapy.

Reversing Multidrug Resistance by Inducing Mitochondrial Dysfunction for Enhanced Chemo-Photodynamic Therapy in Tumor.

Efficiency of standard chemotherapy is dramatically hindered by intrinsic multidrug resistance (MDR). Recently, to amplify therapeutic efficacy, photodynamic therapy (PDT)-induced mitochondrial dysfunction by decorating targeting moieties on nanocarriers has obtained considerable attention. Nevertheless, low targeting efficiency, complex synthesis routes, and difficulty in releasing contents become the major obstacles in further clinical application. Herein, an ingenious liposomal-based nanomedicine (L@BP) was fabricated by encapsulating a mitochondria-anchored photosensitizer (Cy-Br) and paclitaxel (PTX) for realizing enhanced cooperation therapy. At the cellular level, L@BP could hurdle endosomal traps to localize and implement PDT in mitochondria. Intriguingly, the PDT-induced in situ mitochondrial dysfunction led to intracellular ATP reduction, which triggered the downregulated P-glycoprotein transportation capacity and thus resulted in diminishing the efflux of chemotherapeutic agents and increasing drug uptake by drug-resistant cells. The prepared nanomedicine eminently accumulated in the tumor site and acquired enhanced therapeutic efficiency on PTX-resistant lung cancer cells, which possessed great potential in circumventing MDR tumors.

Stimuli-Responsive Polysaccharide Enveloped Liposome for Targeting and Penetrating Delivery of survivin-shRNA into Breast Tumor.

Silencing the inhibitor of apoptosis (IAP) by RNAi is a promising method for tumor therapy. One of the major challenges lies in how to sequentially overcome the system barriers in the course of the tumor targeting delivery, especially in the tumor accumulation and penetration. Herein we developed a novel stimuli-responsive polysaccharide enveloped liposome carrier, which was constructed by layer-by-layer depositing redox-sensitive amphiphilic chitosan (CS) and hyaluronic acid (HA) onto the liposome and then loading IAP inhibitor survivin-shRNA gene and permeation promoter hyaluronidase (HAase) sequentially. The as-prepared HA/HAase/CS/liposome/shRNA (HCLR) nanocarrier was verified to be stable in blood circulation due to the negative charged HA shield. The tumor targeting recognition and the enhanced tumor accumulation of HCLR were visualized by fluorescence resonance energy transfer (FRET) and in vivo fluorescence biodistribution. The deshielding of HA and the protonizing of CS in slightly acidic tumor extracellular pH environment (pHe, 6.8-6.5) were demonstrated by ζ potential change from -23.1 to 29.9 mV. The pHe-responsive HAase release was confirmed in the tumor extracellular mimicking environments, and the intratumoral biodistribution showed that the tumor penetration of HCLR was improved. The cell uptake of HCLR in pHe environment was significantly enhanced compared with that in physiological pH environment. The increased shRNA release of HCLR was approved in 10 mM glutathione (GSH) and tumor cells. Surprisingly, HCLR suppressed the tumor growth markedly through survivin silencing and meanwhile maintained low toxicity to mice. This study indicates that the novel polysaccharide enveloped HCLR is promising in clinical translation, thanks to the stimuli-triggered tumor accumulation, tumor penetration, cell uptake, and intracellular gene release.