{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:31:29Z","timestamp":1785407489118,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005046","name":"Natural Science Foundation of Heilongjiang Province of China","doi-asserted-by":"crossref","award":["PL2024H079"],"award-info":[{"award-number":["PL2024H079"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Horizontal Research Project of the First Affiliated Hospital of Harbin Medical University","award":["2023HX010"],"award-info":[{"award-number":["2023HX010"]}]},{"award":["2023HX010"],"award-info":[{"award-number":["2023HX010"]}],"id":[{"id":"https:\/\/ror.org\/05vy2sc54","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Glioblastoma multiforme (GBM) treatment is limited by tumor hypoxia and poor specificity of therapeutic agents. To address these challenges, we developed brain-targeted liposomes co-encapsulating 5-aminolevulinic acid (5-ALA) and catalase (CAT), termed brain-targeted 5-ALA-CAT liposomes (BACL), which were surface-modified with the Angiopep-2 ligand to enhance blood\u2013brain barrier penetration and achieve multimodal therapy combining targeted delivery and oxygen generation. Methods: BACL was prepared and characterized. Tumor targeting was verified by flow cytometry and in vivo imaging. In vitro antitumor activity was evaluated by wound-healing assay, colony formation assay, live\/dead staining, MTT assay, and Western blotting. In vivo efficacy, apoptosis, and safety were assessed in a subcutaneous xenograft model. Transcriptome sequencing and qRT-PCR were employed to identify molecular mechanisms and novel targets. Results: BACL exhibited favorable physicochemical properties (size: 122.4 nm, PDI: 0.189, zeta potential: \u221212.3 mV) and spherical morphology as observed by TEM, with encapsulation efficiencies of 51.2% for 5-ALA and 43.8% for CAT. Compared with unmodified 5-ALA, BACL increased the cellular uptake efficiency by 1.6-fold in glioma cells while maintaining catalytic stability for sustained oxygen generation. In vitro experiments demonstrated that BACL significantly inhibited glioma cell migration, colony formation, and cell viability, and induced apoptosis. In a subcutaneous xenograft tumor model, BACL-mediated photodynamic therapy (PDT) achieved a tumor growth inhibition rate of 52%, with apoptosis induction via regulation of Bcl-2, Bax, and p53 expression, and no obvious toxicity to major organs was observed. Transcriptomic analysis combined with qRT-PCR validation revealed that BACL activates multiple antitumor signaling pathways, including targeted inhibition of IL-10 and CXCL13 to disrupt cytokine\u2013receptor interactions, as well as coordinated regulation of S100A3 and IGSF-9 expression to suppress glioma progression. Conclusions: These multimodal actions enhanced PDT efficacy while remodeling the tumor microenvironment. Our findings position BACL as a promising therapeutic platform integrating targeted delivery, hypoxia alleviation, and immunomodulation for GBM therapy.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070777","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:52:11Z","timestamp":1782453131000},"page":"777","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Brain-Targeted 5-ALA-CAT Liposomes (BACL) Alleviate Hypoxia and Enhance Photodynamic Therapy in a Murine Glioblastoma Flank Xenograft Model via Angiopep-2-Mediated Targeting"],"prefix":"10.3390","volume":"18","author":[{"given":"Qian","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"},{"name":"Department of Neurosurgical Laboratory, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"},{"name":"Heilongjiang Province Key Laboratory of Precision Pharmaceutical Research, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9086-8126","authenticated-orcid":false,"given":"Yuhang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"},{"name":"Department of Neurosurgical Laboratory, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"},{"name":"Heilongjiang Province Key Laboratory of Precision Pharmaceutical Research, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"},{"name":"Department of Neurosurgical Laboratory, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewen","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"},{"name":"Department of Neurosurgical Laboratory, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danlu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0360-8973","authenticated-orcid":false,"given":"Xin","family":"Hai","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"},{"name":"Heilongjiang Province Key Laboratory of Precision Pharmaceutical Research, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgical Laboratory, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinlei","family":"Yang","sequence":"additional","affiliation":[{"name":"Animal Laboratory Center, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxin","family":"Gou","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunpeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"},{"name":"Department of Neurosurgical Laboratory, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"},{"name":"Department of Neurosurgical Laboratory, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"},{"name":"Heilongjiang Province Key Laboratory of Precision Pharmaceutical Research, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.wneu.2021.03.011","article-title":"Intraoperative MRI for Glioma Surgery: Present Overview and Future Directions","volume":"149","author":"Yahanda","year":"2021","journal-title":"World 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