tirapazamine and phytochlorin

Sonodynamic therapy (SDT) shows tremendous potential to induce immunogenic cell death (ICD) and activate antitumor immunity. However, it can aggravate hypoxia and release platelet (PLT)-associated danger-associated molecular patterns (DAMPs), which impede therapeutic efficacy and promote tumor metastasis. In order to solve these problems, a biomimetic decoy (designated as Lipo-Ce6/TPZ@M

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomimetic Materials; Cell Hypoxia; Cell Line, Tumor; Chlorophyllides; Humans; Liposomes; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Porphyrins; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Tirapazamine; Tissue Distribution; Ultrasonic Therapy; Xenograft Model Antitumor Assays

Hypoxia, a state of low oxygen tension in solid tumors, is not only closely correlated with resistance to both radiotherapy and chemotherapy, but also associated with poor prognosis of tumors and regional lymph node status. Herein, based on the analysis of cell samples from tumor patients, low-density lipoprotein receptor (LDLR) was found to be overexpressed on the surface of hypoxic tumor cell membranes, and confirmed to be an effective hypoxia marker through specific binding with anti-LDLR antibody in solid tumors. In addition, using the special therapeutic microenvironment of hypoxia, tirapazamine (TPZ, which can be used as both a hypoxia-activated chemotherapy prodrug and radiotherapy sensitizer) was integrated with PEGylated photosensitizer chlorin e6 (Ce6-PEG) by self-assembly, and anti-LDLR was then modified on the surface to form tumor hypoxia-targeting multifunctional nanoparticles (CPTA). CPTA possesses a multimodal antitumor effect via a simultaneous photothermal therapy (PTT)/photodynamic therapy (PDT) effect generated by Ce6, and chemotherapy/radiotherapy actions sensitized by TPZ. It is noteworthy that tumor oxygen was consumed in the process of PDT and the hypoxia was subsequently exacerbated, which can greatly increase the TPZ-sensitized chemotherapy and lead to a synergistic antitumor effect. Both in vitro and in vivo experiments demonstrated that CPTA possesses an excellent therapeutic effect through PTT, PDT, and TPZ sensitized radiotherapy and chemotherapy. This hypoxic tumor targeting synergetic therapeutic strategy has great potential for future clinical transformation.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chlorophyllides; Drug Screening Assays, Antitumor; Humans; Ligands; Materials Testing; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental; Particle Size; Photochemotherapy; Photosensitizing Agents; Photothermal Therapy; Polyethylene Glycols; Porphyrins; Receptors, LDL; Surface Properties; Tirapazamine; Tumor Hypoxia

Photodynamic therapy (PDT), as an essential tumor treatment method, has received great attention; however, there are still some challenges such as hydrophobicity of most of the photosensitizers, safety of in vivo transport, and characteristics of oxygen consumption. Herein, we used albumin as the nanocarrier for the loading of Chlorin e6 (Ce6) photosensitizer. In the meantime, tirapazaming (TPZ) was co-loaded onto the nanocomposite, which could be activated by hypoxia caused by PDT for enhanced therapy. Considering the over irradiation problem, a strategy for measuring PDT degree by ratio fluorescence was utilized. The PDT monitoring design relies on ratio emissions of C6 (Coumarin 6) and Ce6 molecules since the red emission of Ce6 is dependent on the PDT capability. Based on the characterization of the albumin nanocomposites, we further explored the combined therapy effect at both the in vitro and in vivo levels and attained the corresponding results.

Topics: Animals; Cattle; Cell Line, Tumor; Cell Survival; Chlorophyllides; Coumarins; Humans; Light; Liver; Mice; Microscopy, Confocal; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Serum Albumin, Bovine; Thiazoles; Tirapazamine; Transplantation, Homologous

Hypoxia tumor microenvironment is a major challenge for photodynamical therapy (PDT), and hypoxia-activated chemotherapy combined PDT could be promising for enhanced anticancer therapy. In this study, we report an innovative 2-nitroimidazole derivative conjugated polyethylene glycol (PEG) amphoteric polymer theranostic liposome encapsulated a photosensitizer Chlorin e6 (Ce6), hypoxia-activated prodrug Tirapazamine (TPZ) and gene probe for synergistic photodynamic-chemotherapy. Ce6-mediated PDT upon irradiation with a laser induces hypoxia, which leads to the disassembly of the liposome and activates the antitumor activity of TPZ for improved cancer cell-killing. The released co-delivered gene probe could effectively detect the oncogenic intracellular biomarker for diagnosis. Both in vitro and in vivo studies demonstrated the greatly improved anti-cancer activity compared to conventional PDT. This work contributes to the design of hypoxia-responsive multifunctional liposome for tumor diagnosis and hypoxia-activated chemotherapy combined PDT for synergetic therapy, which holds great promise for future cancer therapy.

Topics: Animals; Antineoplastic Agents; Chlorophyllides; Delayed-Action Preparations; Humans; Light; Liposomes; MCF-7 Cells; Mice; Neoplasms; Nitroimidazoles; Optical Imaging; Photosensitizing Agents; Polyethylene Glycols; Porphyrins; Theranostic Nanomedicine; Tirapazamine; Tumor Hypoxia