Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood‒brain barrier

Glioblastoma (GBM) is the most aggressive malignant brain tumor and has a high mortality rate. Photodynamic therapy (PDT) has emerged as a promising approach for the treatment of malignant brain tumors. However, the use of PDT for the treatment of GBM has been limited by its low blood‒brain barrier (BBB) permeability and lack of cancer-targeting ability. Herein, brain endothelial cell-derived extracellular vesicles (bEVs) were used as a biocompatible nanoplatform to transport photosensitizers into brain tumors across the BBB. To enhance PDT efficacy, the photosensitizer chlorin e6 (Ce6) was linked to mitochondria-targeting triphenylphosphonium (TPP) and entrapped into bEVs. TPP-conjugated Ce6 (TPP-Ce6) selectively accumulated in the mitochondria, which rendered brain tumor cells more susceptible to reactive oxygen species-induced apoptosis under light irradiation. Moreover, the encapsulation of TPP-Ce6 into bEVs markedly improved the aqueous stability and cellular internalization of TPP-Ce6, leading to significantly enhanced PDT efficacy in U87MG GBM cells. An in vivo biodistribution study using orthotopic GBM-xenografted mice showed that bEVs containing TPP-Ce6 [bEV(TPP-Ce6)] substantially accumulated in brain tumors after BBB penetration via transferrin receptor-mediated transcytosis. As such, bEV(TPP-Ce6)-mediated PDT considerably inhibited the growth of GBM without causing adverse systemic toxicity, suggesting that mitochondria are an effective target for photodynamic GBM therapy.

Enzyme-instructed and mitochondria-targeting peptide self-assembly to efficiently induce immunogenic cell death

Immunogenic cell death (ICD) plays a major role in cancer immunotherapy by stimulating specific T cell responses and restoring the antitumor immune system. However, effective type II ICD inducers without biotoxicity are still very limited. Herein, a tentative drug- or photosensitizer-free strategy was developed by employing enzymatic self-assembly of the peptide F-pY-T to induce mitochondrial oxidative stress in cancer cells. Upon dephosphorylation catalyzed by alkaline phosphatase overexpressed on cancer cells, the peptide F-pY-T self-assembled to form nanoparticles, which were subsequently internalized. These affected the morphology of mitochondria and induced serious reactive oxygen species production, causing the ICD characterized by the release of danger-associated molecular patterns (DAMPs). DAMPs enhanced specific immune responses by promoting the maturation of DCs and the intratumoral infiltration of tumor-specific T cells to eradicate tumor cells. The dramatic immunotherapeutic capacity could be enhanced further by combination therapy of F-pY-T and anti-PD-L1 agents without visible biotoxicity in the main organs. Thus, our results revealed an alternative strategy to induce efficient ICD by physically promoting mitochondrial oxidative stress.

A mitochondria-targeting lipid-small molecule hybrid nanoparticle for imaging and therapy in an orthotopic glioma model

Hybrid lipid‒nanoparticle complexes have shown attractive characteristics as drug carriers due to their integrated advantages from liposomes and nanoparticles. Here we developed a kind of lipid-small molecule hybrid nanoparticles (LPHNPs) for imaging and treatment in an orthotopic glioma model. LPHNPs were prepared by engineering the co-assembly of lipids and an amphiphilic pheophorbide a‒quinolinium conjugate (PQC), a mitochondria-targeting small molecule. Compared with the pure nanofiber self-assembled by PQC, LPHNPs not only preserve the comparable antiproliferative potency, but also possess a spherical nanostructure that allows the PQC molecules to be administrated through intravenous injection. Also, this co-assembly remarkably improved the drug-loading capacity and formulation stability against the physical encapsulation using conventional liposomes. By integrating the advantages from liposome and PQC molecule, LPHNPs have minimal system toxicity, enhanced potency of photodynamic therapy (PDT) and visualization capacities of drug biodistribution and tumor imaging. The hybrid nanoparticle demonstrates excellent curative effects to significantly prolong the survival of mice with the orthotopic glioma. The unique co-assembly of lipid and small molecule provides new potential for constructing new liposome-derived nanoformulations and improving cancer treatment.

Advances in novel anti-neurodegenerative diseases drugs targeting mitochondria / 国际药学研究杂志

Mitochondria,the major organelle in neurons,which provides energy via oxidative phosphorylation for all kinds of metabolic activities,is involved in many pathophysiological processes,such as calcium homeostasis and apoptosis. Increasing evi?dence has indicated that mitochondrial dysfunction displays a significant role in the early stage of neurodegenerative disorders like Par?kinson′s disease(PD)and Alzheimer′s disease(AD). Therefore,studies which focus on mitochondrial dysfunction under these patho?logical conditions contribute to understanding the pathogenesis of neurodegenerative disorder and discovering new neuroprotective drugs. Actually,various mitochondria-targeting agents have been tried in clinic or under different investigational phases against neuro?degenerative disorders. This review discusses the evidence on mitochondrial impairments during neurodegenerative diseases and the advances in mitochondria-targeting agents as a potential alternative drug strategy for effective management of neurodegenerative diseases.

Advances in novel anti-neurodegenerative diseases drugs targeting mitochondria / 国际药学研究杂志

Mitochondria, the major organelle in neurons, which provides energy via oxidative phosphorylation for all kinds of metabolic activities, is involved in many pathophysiological processes, such as calcium homeostasis and apoptosis. Increasing evidence has indicated that mitochondrial dysfunction displays a significant role in the early stage of neurodegenerative disorders like Parkinson’s disease(PD)and Alzheimer’s disease(AD). Therefore, studies which focus on mitochondrial dysfunction under these pathological conditions contribute to understanding the pathogenesis of neurodegenerative disorder and discovering new neuroprotective drugs. Actually, various mitochondria-targeting agents have been tried in clinic or under different investigational phases against neurodegenerative disorders. This review discusses the evidence on mitochondrial impairments during neurodegenerative diseases and the advances in mitochondria-targeting agents as a potential alternative drug strategy for effective management of neurodegenerative diseases.