Tirapazamine encapsulated hyaluronic acid nanomicelles realized targeted and efficient photo-bioreductive cascading cancer therapy (2023)

Alzheimer's disease is a neurodegenerative disease that signals for excess β-amyloid (Aβ) aggregation. Although people have made great attempts to control the aggregation of Aβ, no effective medications have been produced yet. Due to its excellent temporal and spatial selectivity, photodynamic treatment has been gradually employed and interfered in the aggregation process of Aβ, with some achievement. To enhance the research and application of photodynamic therapy in Alzheimer's disease, this paper reviews the progress of small-molecule photosensitizers in the treatment of Alzheimer's disease in recent years and outlines existing tactics and potential obstacles.

Radioresistance of Cancer stem cell (CSC) is an important cause of tumor recurrence after radiotherapy (RT). Herein, we designed a type I aggregation-induced emission (AIE) photosensitiser-loaded biomimetic mesoporous organosilicon nanosystem (PMT) for precise depletion of CSC to prevent tumor recurrence after RT. This PMT system is composed of a type I AIE photosensitiser (TBP-2) loaded mesoporous organosilicon nanoparticles (MON) with an outer platelet membrane. The PMT system is able to specifically target CSC. Intracellular glutathione activity leads to MON degradation and the release of TBP-2. Type I photodynamic therapy is activated by exposure to white light, producing a large amount of hydroxyl radicals to promote CSC death. The results of in vivo experiments demonstrated specific removal of CSC following PMT treatment, with no tumor recurrence observed when combined with RT. However, tumor recurrence was observed in mice that received RT only. The expression of CSC markers was significantly reduced following PMT treatment. We demonstrate the development of a system for the precise removal of CSC with good biosafety and high potential for clinical translation. We believe the PMT nanosystem represents a novel idea in the prevention of tumor recurrence.

Hypoxic tumor microenvironment is a major challenge for photodynamic therapy (PDT). To overcome this problem, PDT combined hypoxia-activated chemotherapy is a promising strategy for hypoxic cancer therapy. Herein, a multifunctional liposome (AQ4N-Ir1-sorafenib-liposome) is prepared by encapsulating a hypoxia-activated prodrug AQ4N, a photosensitizer iridium(III) complex and hepatocellular carcinoma (HCC) targeting drug sorafenib, for synergistic therapy of HCC. Ir1-mediated PDT upon irradiation induces ROS generation and hypoxic environment, which leads to the disassembly of the liposome and activates the antitumor activity of AQ4N. Meantime, the co-delivered sorafenib could effectively target therapy of HCC. It is noted that ferroptosis mechanism is proved during the treatment. This work contributes to the design of hypoxia-responsive multifunctional liposome for combination of chemotherapy, targeting therapy and PDT. It is a promising strategy for hypoxic HCC therapy.

Owing to elegant biomacromolecule features, proteins have been investigated to prepare a multifunctional and targeted nanoscale drug delivery systems. In this work, a novel cationic protein based nanocarrier, AS1411 aptamer-conjugated poly-l-lysine/β-lactogolubolin nanoparticles (BNP/PLL/Apt), was fabricated. The as-prepared nanocarrier offers an innovative formulation that combines the outstanding properties of protein nanocarriers and aptamer as a targeting agent for chemotherapy. To demonstrate the therapeutic potential of BNP/PLL/Apt, the nanocarriers were loaded with doxorubicin (DOX). The DOX-loaded BNP/PLL/Apt ([emailprotected]/PLL/Apt) exhibited high drug encapsulation efficiency, as high as 92%, and the controlled drug release profile in a mildly acidic physiological condition that could enhance therapeutic efficiency in cancerous cells. The in vitro assays of [emailprotected]/PLL/Apt illustrated that the synthesized drug delivery system was hemocompatible based on hemagglutination, coagulation and complement activation assay results. Besides, [emailprotected]/PLL/Apt was more potent against MCF-7 tumor cells than the free DOX. Thanks to the particular recognition between AS1411 aptamer and its receptor over-expressed on cancer cells, the BNP/PLL/Apt NPs show the enhanced cellular uptake in MCF-7cells compared with the BNPs without aptameric modification. Moreover, the computational studies exhibited the reasonable binding affinity of β-lactogolubolin to DOX and activity of AS1411 aptamer against cancer cells which confirmed the experimental results. Overall, the resultants of this research possessed numerous advantages of [emailprotected]/PLL/Apt over free chemotherapy drugs and confirmed its great potential to address the clinical challenges observed in targeted anticancer drug delivery system.

Chemotherapy is one of the most commonly used treatment regimens for malignant tumors. However, the clinical outcomes of chemotherapy alone are still far from satisfactory, due to the insufficient therapeutic effect and serious side effects. Chemo-phototherapy, with the excellent advantages of synergetic treatment effect and dosage reduction of chemotherapeutics, has received wide attention in multimodal cancer therapy. Prodrug-engineered nanosystems, integrating prodrug strategy with biomedical nanotechnology, offer many benefits for efficient combination drug delivery. In recent years, a wide variety of prodrug-engineered nanomedicines have been developed for efficient chemo-phototherapy. In this review, we intend to outline the latest trends in this field, with a special focus on polymeric prodrug-nanosystems, prodrug/drug co-encapsulation nanocarriers and small-molecule prodrug-nanoassemblies. This review highlights the design rationale, advantages and challenges of the emerging prodrug-engineered nanomedicines in synergistic chemo-phototherapy.

Applied Materials Today, Volume 23, 2021, Article 100995

Nanoscaled metal organic frameworks have emerged as a novel type of organic-inorganic hybrid coordination polymeric nanomaterials and showed great promise in biomedical area in recent decades. As a special subclass, zeolitic imidazolate frameworks (ZIFs), constructing with metal ions and imidazolate linkers, own unique advantages of high porosity, large surface area, good biocompatibility, pH sensitivity and etc. These render ZIFs as attractive and promising platforms to delivery various cargos of drugs, imaging probes and biomacromolecules for cancer diagnosis and therapy. And this review specially summaries the state-of-the-art research on ZIFs for biosensing, cancer imaging and phototheranostics within the latest 5 years. The multiply strategies of synthesis, characterization and functionalization of ZIFs-based nanosystems are firstly discussed. The vital roles of ZIFs in biosensors, including electrochemical, fluorescent and colorimetric sensors are analyzed. Then, the monomodal and/or multimodal cancer imaging techniques mediated by ZIFs are addressed. Particular emphasis is placed on the ZIFs-based cancer phototheranostics which provide a potential alternative avenue to greatly improve the therapeutic index of cancer. Finally, the future opportunities and challenges of ZIFs are tentatively proposed and discussed from the point of translational medicine.

Acta Pharmaceutica Sinica B, Volume 12, Issue 6, 2022, pp. 2695-2709

Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance. Herein, a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms. A disulfide bond-linked bispecific prodrug of NLG919 and JQ1 (namely NJ) was synthesized and self-assembled into a prodrug nanoparticle, which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ. Upon tumor accumulation via passive tumor targeting, the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug. NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond. JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1. In contrast, NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment, which thus restores robust antitumor immune responses. Photodynamic therapy (PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells. The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.

Chemical Engineering Journal, Volume 441, 2022, Article 135993

Precise manipulation of reactive oxygen species (ROS) breakthrough threshold exhibits great potential in destroying solid tumors, reprogramming “immune-cold” tumor and potentiating immunotherapy. However, it is still challenging to develop efficient ROS initiation devices. Herein, we propose a pioneering “grafting from” drug coordination polymerization strategy and develop a fully-coordinated and full-active Cu₂O/drug core/shell nanoparticles for multimodal cancer therapy. Chemotherapeutic drug cisplatin (CDDP) and photosensitizer indocyanine green (ICG) were loaded onto the surface of hydrazided hyaluronic acid-decorated Cu₂O (HA-Cu₂O) nanoparticles through an infinite hydrazide-cisplatin-sulfonic acid coordination mechanism, obtaining CDDP/ICG-coloaded HA-Cu₂O (HCCI) nanoplatform. The HCCI nanoplatform exhibited a rapid acid-responsive dissociation behavior and released ICG, Cu⁺ and CDDP to achieve efficient triple combined photodynamic therapy/chemodynamic therapy/chemotherapy. Importantly, such a combination induced efficient immunogenic cell death cascade mediated by powerful ROS storm to reprogram “immune-cold” tumors and potentiate immunotherapy. The combination of HCCI nanoplatform and αPD-1 not only eradicated primary tumors but effectively inhibited distal tumor growth, lung metastasis and tumor recurrence through reprogramming tumor microenvironment and activating CD8⁺ T cell antitumor immunity. Collectively, we have presented a drug coordination polymerization loading strategy to develop a robust multimodal antitumor nanoplatform, and this study provides a new direction for the design of nanodrug delivery systems.

Chemical Engineering Journal, Volume 403, 2021, Article 126305

Inspired by unique selectivity and irreversible destruction toward treated tissues or cells, photodynamic therapy (PDT) has gained increasing attention in cancer treatment. However, PDT-induced hypoxia and elevated glutathione (GSH) levels in cancer cells are still great challenges which can significantly reduce treatment outcomes. Herein, we designed a GSH-activatable nitric oxide (NO) generating mannan nanoparticles (NO-mannan), an “All in One” therapy nanoplatform with enhanced reactive oxygen species (ROS) generation through GSH depletion and hypoxia relief. Upon reaching the reductive hypoxic tumor microenvironment, the nanoplatform could undergo a GSH-triggered hydrophobic to hydrophilic transition and simultaneously generate NO gas with vessel-relaxing and GSH scavenging for efficient ROS production. Notably, the NO induced hypoxia relief and redox-responsive cellular antioxidant defense system destruction endowed the NO-mannan with the ability of enhanced photodynamic therapy both in vitro and in vivo. Overall, our work demonstrated a simple strategy to combine the GSH responsive NO-based gas therapy with PDT to greatly improve the PDT efficacy especially for hypoxic solid tumors, which may provide a practical paradigm for effective PDT cancer treatment.

Biomaterials, Volume 142, 2017, pp. 149-161

Modulating tumor microenvironment to amplify the therapeutic efficiency would be a novel strategy for effective cancer treatment. In this work, based on the TPZ-loaded porphyrinic metal organic framework PCN-224 (PCN stands for porous coordination network), a cancer cell membrane-coated nanoplatform ([emailprotected]@Mem) was fabricated for tumor targeted PDT and the successively resulting hypoxia-amplified bioreductive therapy. After administration, [emailprotected]@Mem exhibited the selective accumulation and long-term retention at tumor tissue due to the immune escape and homologous targeting endowed by the cancer membrane coating. Upon light irradiation, PCN-224-mediated toxic reactive oxygen species (ROS) were generated for PDT, and the resulting local hypoxia microenvironment would further accelerate the activation of TPZ for enhanced chemotherapy in 4T1 orthotopic tumor. The cascade synergistic therapeutic effects of [emailprotected]@Mem could significantly suppress the primary tumor growth, and also inhibit its distal metastasis with minimal side effects. The study indicated an overwhelming superiority of utilizing this bioinspired strategy for tumor targeted PDT and hypoxia-activated bioreductive therapy, which provided a new insight for precise and effective tumor treatment.

Journal of Colloid and Interface Science, Volume 609, 2022, pp. 353-363

Most carrier-based nano drug delivery systems (nano-DDSs) are subjected to complex preparation or purification processes, metabolic instability and potential systemic toxicity. To overcome these issues, it is urgent to develop a multifunctional carrier-free nano-DDS that can be fabricated by a simple approach for enhanced anticancer efficacy. In this work, the carrier-free supramolecular nanoprodrug (CF SNPD) based on lactose (Lac) functionalized dimeric camptothecin (CPT) was developed, in which Lac and CPT were conjugated by the aromatized thioacetal (ATA, a reactive oxygen species (ROS)-responsive bond). The obtained Lac-ATA-CPT₂ prodrug and the photosensitizer Chlorin e6 (Ce6) formed CF SNPD (denoted as [emailprotected]₂ NPs) in water by supramolecular self-assembly. The design of dimeric CPT endowed [emailprotected]₂ NPs with ultrahigh drug-loading capacity (up to 94%) and excellent stability. The Lac-functionalized CF SNPD displayed active specific targetability to HepG2 cells resulting from the carbohydrate-protein interactions. Furthermore, the fluorescence signal of Ce6 facilitated the precise tracking and localization of [emailprotected]₂ NPs within the cell. Meanwhile, the ROS generated by Ce6 not only cleaved ATA linker to trigger on-demand CPT release, but also exhibited a killing effect on tumor cells, enabling synergistic therapy via CPT-mediated chemotherapy (CT) and Ce6-induced photodynamic therapy (PDT). Therefore, the multifunctional CF SNPD may be one of the promising therapeutic options for liver cancer.