Search

Background: Nanotheranostics advances anticancer management by providing therapeutic and diagnostic functions, that combine programmed cell death (PCD) initiation and imaging-guided treatment, thus increasing the efficacy of tumor ablation and efficiently fighting against cancer. However, mild photothermal/radiation therapy with imaging-guided precise mediating PCD in solid tumors, involving processes related to apoptosis and ferroptosis, enhanced the effect of breast cancer inhibition is not fully understood. Results: Herein, targeted peptide conjugated gold nano cages, iRGD-PEG/AuNCs@FePt NPs ternary metallic nanoparticles (Au@FePt NPs) were designed to achieve photoacoustic imaging (PAI)/Magnetic resonance imaging (MRI) guided synergistic therapy. Tumor-targeting Au@FePt forms reactive oxygen species (ROS), initiated by X-ray-induced dynamic therapy (XDT) in collaboration with photothermal therapy (PTT), inducing ferroptosis-augmented apoptosis to realize effective antitumor therapeutics. The relatively high photothermal conversion ability of Au@FePt increases the temperature in the tumor region and hastens Fenton-like processes to achieve enhanced synergistic therapy. Especially, RNA sequencing found Au@FePt inducting the apoptosis pathway in the transcriptome profile. Conclusion: Au@FePt combined XDT/PTT therapy activate apoptosis and ferroptosis related proteins in tumors to achieve breast cancer ablation in vitro and in vivo. PAI/MRI images demonstrated Au@FePt has real-time guidance for monitoring synergistic anti-cancer therapy effect. Therefore, we have provided a multifunctional nanotheranostics modality for tumor inhibition and cancer management with high efficacy and limited side effects. [ABSTRACT FROM AUTHOR]

As most solid tumors are characterized by a hypoxic microenvironment, enormous efforts have been made to develop strategies to fight hypoxia. This study shows that ivermectin (IVM), an antiparasitic drug, is able to alleviate tumor hypoxia by inhibiting mitochondrial respiration. We explore this to strengthen oxygen-dependent photodynamic therapy (PDT) using chlorin e6 (Ce6) as a photosensitizer. To synergize their pharmacological behaviors, Ce6 and IVM are encapsulated into stable Pluronic F127 micelles. The micelles are uniform in size and seem well-suited for the co-delivery of Ce6 and IVM. The micelles could passively target the drugs into tumors and enhance their cellular internalization. Most importantly, through mitochondrial dysfunction, the micelles reduce the oxygen consumption (making the tumor less hypoxic). Consequently, the production of reactive oxygen species would be increase which, in turn, improves the efficacy of PDT against hypoxic tumors. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Tumor vascular blockade is a promising strategy for adjuvant cancer treatment. In this work, a self-delivery nanomedicine is developed based on a vascular disruptor and photosensitizer for tumor synergistic therapy. Specifically, this nanomedicine (designated as CeCA) is comprised of combretastatin A4 (CA4) and chlorine e6 (Ce6) by self-assembly technique. Among which, CA4 could not only induce tubulin inhibition for chemotherapy but also disrupt the vasculature to cause tumor hemorrhage. Moreover, Ce6 is able to generate lots of singlet oxygen (1O 2) for synergistic photodynamic therapy (PDT) under light irradiation. It is interesting that the carrier-free CeCA possessed a favorable stability and an improved cellular uptake behavior. After intravenous administration, CeCA prefers to accumulate at tumor site for vascular disruption-supplemented chemo-photodynamic therapy. Notably, CeCA is prepared without additional carriers, which avoids the system toxicity raised by excipients. Consequently, CeCA greatly inhibits the tumor growth and leads to a low side effect in vivo. It might open a window in the development of self-supplementary nanomedicine for synergistic tumor treatment. [ABSTRACT FROM AUTHOR]

• Construction of a stable ternary biomedicine without extra drug excipient. • Upregulating NLRP3 to promote PDT induced cell pyroptosis. • Immune activation by pyroptosis induction and IDO inhibition for tumor inhibition. The development of immunotherapy is seriously limited by the insufficient tumor immunogenicity and immunosuppressive microenvironment. Pyroptosis is a new form of immunogenic cell death (ICD) associated with the gasdermin protein family, which has received increasing attention as a promising approach to activate antitumor immunity. Herein, we construct a ternary biomedicine (CNS) based on the self-assembly of photosensitizer chlorine e6 (Ce6), NLG919 (NLG) and simvastatin (Sim), which has a fairly high drug content, good stability and uniform morphology. Interestingly, the photodynamic therapy of CNS can generate reactive oxygen species (ROS) to induce intracellular oxidative stress, activating NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/Caspase-1 (Cas-1)/gasdermin D N-terminal domain (GSDMD-N) dependent pyroptosis. Further, Sim-mediated NLRP3 upregulation will also promote cell pyroptosis to activate ICD and stimulate immune responses. Benefiting from NLG-induced indoleamine 2,3-dioxygenase (IDO) inhibition, CNS is capable of improving the immunosuppressive microenvironment to enhance immunotherapy. Consequently, the pyroptosis induction synergized with IDO inhibition of CNS exhibits excellent antitumor immune activities, as evidenced by enhancing DCs maturation and effector memory T cells frequency, which significantly inhibit tumor growth and metastasis. This proposal of self-delivery ternary nanomedicine might open a new window to construct drug delivery systems for pyroptosis activated immunotherapy. [ABSTRACT FROM AUTHOR]

Tumor cells are characterized by unlimited proliferation and escape of immune clearance, which are closely associated with the down regulation of surface antigens. In this work, a carrier free photodynamic modulator (CeTaz) is developed to improve immunosuppressive tumor microenvironment and promote the recognition of tumors by T cells by epigenetic reprogramming. Specifically, CeTaz is assembled by chlorine e6 (Ce6) and tazemetostat (Taz) through intermolecular interactions. Upon light irradiation, CeTaz is able to promote the generation of reactive oxygen species (ROS) for a robust photodynamic therapy (PDT) to inhibit localized tumor growth. Meanwhile, the PDT also induces immunogenic cell death (ICD) to initiate immune response, leading to the activation of effector T cells. More importantly, CeTaz could inhibit the epigenetic regulator of EZH2 to suppress the methylation of H3K27, which would promote tumor cells to express MHC-I and release CXCL10. Consequently, the epigenetically reprogrammed tumor cells are readily recognized by effector T cells to enhance the antitumor immunity. Results indicate that the PDT activated immunotherapy of CeTaz could simultaneously inhibit the growth of primary and distant tumors with a low system toxicity. This study would advance the development of carrier free nanomedicine for precise treatment of metastatic tumor. [ABSTRACT FROM AUTHOR]

• Self-delivery nanomedicine of PyroR was prepared without drug-excipients. • PyroR could enhance the stability and facilitate the delivery of photosensitizers and TLR agonists. • Photodynamic therapy (PDT) of PyroR could efficiently inhibit primary tumor growth and initiate immunological cascade. • PryoR could repolarize M2 macrophages into M1 phenotype for immunotherapy against metastatic tumors. Immunotherapy is a promising clinical treatment strategy against malignant tumor metastasis, however, it often shows an inadequate efficacy owing to the immunosuppressive tumor microenvironment (ITM). Herein, we develop a self-delivery re-educator to induce immunogenic cell death (ICD) and macrophage polarization for photodynamic therapy (PDT) and immunotherapy against breast cancer. To be specific, the self-delivery re-educator (designated as PyroR) is prepared by the self-assembly of the photosensitizer pyropheophorbide-a (Pyro) and TLR agonist resiquimod (R848). Without any carriers, nanosized PyroR exhibits high drug contents and could avoid the side effects raised by excipients. After intravenous administration, PyroR could generate a lot of reactive oxygen species (ROS) for PDT against primary tumor in the presence of light irradiation. Meanwhile, PDT triggered ICD cascade would promote dendritic cells (DCs) maturation and activate cytotoxic T lymphocytes (CTLs) for immunotherapy against distant and metastatic tumors. More importantly, R848 is able to polarize macrophages from M2 to M1 phenotype, which would improve the ITM to enhance antitumor immunity. Consequently, the PDT-initiated immunotherapy of PyroR demonstrates significant inhibition effects on primary, distant and metastatic tumors while causes a minimal system toxicity. This self-delivery re-educating strategy would shed light on constructing carrier-free nanomedicine for treatment of malignant tumors. [ABSTRACT FROM AUTHOR]