ABSTRACT
Antiangiogenic therapy is an effective way to disrupt nutrient supply and starve tumors, but it is restricted by poor efficacy and negative feedback-induced tumor relapse. In this study, a neuropilin-1 (NRP-1)-targeted nanomedicine (designated as FPPT@Axi) is reported for spatiotemporal tumor suppression by combining photodynamic therapy (PDT) with antiangiogenesis. In brief, FPPT@Axi is prepared by utilizing an NRP-1-targeting chimeric peptide (Fmoc-K(PpIX)-PEG8-TKPRR) to encapsulate the antiangiogenic drug Axitinib (Axi). Importantly, the NRP-1-mediated targeting property enables FPPT@Axi to selectively concentrate at vascular endothelial and breast cancer cells, facilitating the production of reactive oxygen species (ROS) in situ for specific vascular disruption and enhanced cell apoptosis under light stimulation. Moreover, the codelivered Axi can further inhibit vascular endothelial growth factor receptor (VEGFR) to impair the negative feedback of PDT-induced tumor neovascularization. Consequently, FPPT@Axi spatiotemporally restrains the tumor growth through blocking angiogenesis, destroying tumor vessels, and inducing tumor apoptosis. Such an NRP-1-mediated targeting codelivery system sheds light on constructing an appealing candidate with translational potential by using clinically approved PDT and chemotherapy.
Subject(s)
Angiogenesis Inhibitors , Neovascularization, Pathologic , Neuropilin-1 , Photochemotherapy , Neuropilin-1/metabolism , Humans , Animals , Mice , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/chemistry , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Female , Axitinib/pharmacology , Axitinib/chemistry , Axitinib/therapeutic use , Nanomedicine , Apoptosis/drug effects , Human Umbilical Vein Endothelial Cells , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Mice, Inbred BALB C , Cell Line, Tumor , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/therapeutic use , Reactive Oxygen Species/metabolism , Mice, NudeABSTRACT
Cancer-associated fibroblasts (CAFs) assist in breast cancer (BRCA) invasion and immune resistance by overproduction of extracellular matrix (ECM). Herein, we develop FPC@S, a photodynamic immunomodulator that targets the ECM, to improve the photodynamic immunotherapy for fibrotic BRCA. FPC@S combines a tumor ECM-targeting peptide, a photosensitizer (protoporphyrin IX) and an antifibrotic drug (SIS3). After anchoring to the ECM, FPC@S causes ECM remodeling and BRCA cell death by generating reactive oxygen species (ROS) in situ. Interestingly, the ROS-mediated ECM remodeling can normalize the tumor blood vessel to improve hypoxia and in turn facilitate more ROS production. Besides, upon the acidic tumor microenvironment, FPC@S will release SIS3 for reprograming CAFs to reduce their activity but not kill them, thus inhibiting fibrosis while preventing BRCA metastasis. The natural physical barrier formed by the dense ECM is consequently eliminated in fibrotic BRCA, allowing the drugs and immune cells to penetrate deep into tumors and have better efficacy. Furthermore, FPC@S can stimulate the immune system and effectively suppress primary, distant and metastatic tumors by combining with immune checkpoint blockade therapy. This study provides different insights for the development of fibrotic tumor targeted delivery systems and exploration of synergistic immunotherapeutic mechanisms against aggressive BRCA.
Subject(s)
Breast Neoplasms , Cancer-Associated Fibroblasts , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cancer-Associated Fibroblasts/metabolism , Reactive Oxygen Species/metabolism , Extracellular Matrix/metabolism , Immunotherapy , Fibrosis , Tumor MicroenvironmentABSTRACT
Ephedrine (EPH) is an alkaloid commonly used to relieve nasal congestion caused by colds, allergic rhinitis, rhinitis, and sinusitis, and to control bronchial asthma. It is also be used as a raw material in the manufacture of methamphetamine. Although the distribution of EPH in surface waters has been widely studied, its uptake, internal distribution, and toxicokinetic processing in exposed organisms have not been well investigated. In this study, we investigated the uptake, disposition, and toxicokinetics of EPH in zebrafish (Danio rerio) in a semi-static exposure system. EPH was consistently detected in zebrafish biological samples, with the highest concentrations of 84.97 ng·g-1 detected in the brain tissue of fish in the high treatment group. Over the 14-d exposure period, the relative abundance of mean concentrations of EPH in biological samples generally followed the order of brain > ovary > liver > intestine > muscle. The uptake rate constants (Ku), elimination rate constants (Ke), and half-lives of EPH in the biological tissues were in the ranges 0.23-570.31 L·(kg·d)-1, 1.22-6.11 d-1, and 0.12-0.57 d, respectively. The observed bioconcentration factor (BCFo) and kinetically-derived bioconcentration factor (BCFk) were similar, ranging 0.24-337.33 L·kg-1 and 0.13-316.43 L·kg-1, respectively. These results are helpful for understanding the behavior of psychoactive substances in aquatic organisms and have directive significance for studying their toxicity and ecological risks to aquatic organisms.
