Radiation and adjuvant drug-loaded liposomes target glioblastoma stem cells and trigger in-situ immune response
| Autor: | Francesco DiMeco, Beatrice Formicola, Marco Pizzocri, Elisabetta Stanzani, Francesca Re, Federica Ungaro, Eliana Lauranzano, Michela Matteoli, Maria Gregori, Simona Rodighiero, Matteo Tamborini, Alessandro Perin, Lorena Passoni, Massimo Masserini, Maura Francolini |
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| Přispěvatelé: | Pizzocri, M, Re, F, Stanzani, E, Formicola, B, Tamborini, M, Lauranzano, E, Ungaro, F, Rodighiero, S, Francolini, M, Gregori, M, Perin, A, Dimeco, F, Masserini, M, Matteoli, M, Passoni, L |
| Rok vydání: | 2021 |
| Předmět: |
endocrine system
glioblastoma stem cell drug-loaded liposomes Population blood–brain barrier Immune system immunogenic cell death medicine AcademicSubjects/MED00300 Doxorubicin education radiotherapy education.field_of_study Microglia business.industry glioblastoma liposome Acquired immune system medicine.anatomical_structure Transcytosis Basic and Translational Investigations Cancer research Immunogenic cell death AcademicSubjects/MED00310 Stem cell business medicine.drug |
| Zdroj: | Neuro-oncology Advances |
| ISSN: | 2632-2498 |
| Popis: | Background The radio- and chemo- resistance of Glioblastoma Stem-like Cells (GSCs), together with their innate tumor-initiating aptitude, make this cell population a crucial target for effective therapies. However, targeting GSCs is hardly difficult and complex, due to the presence of the Blood Brain Barrier (BBB) and the infiltrative nature of GSCs arousing their dispersion within the brain parenchyma. Methods Liposomes (LIPs), surface-decorated with an Apolipoprotein E-derived peptide (mApoE) to enable BBB crossing, were loaded with doxorubicin (DOXO), as paradigm of cytotoxic drug triggering immunogenic cell death (ICD). Patient-derived xenografts (PDXs) obtained by GSC intracranial injection were treated with mApoE-DOXO-LIPs alone or concomitantly with radiation. Results Our results indicated that mApoE, through the engagement of the Low-Density Lipoprotein Receptor (LDLR), promotes mApoE-DOXO-LIPs transcytosis across the BBB and confers target specificity towards GSCs. Irradiation enhanced LDLR expression on both BBB and GSCs, thus further promoting LIP diffusion and specificity. When administered in combination with radiations, mApoE-DOXO-LIPs caused significant reduction of in vivo tumor growth due to GSC apoptosis. GSC apoptosis prompted microglia/macrophage phagocytic activity, together with the activation of the antigen-presenting machinery crucially required for anti-tumor adaptive immune response. Conclusions Our results advocate for radiotherapy and adjuvant administration of drug-loaded, mApoE-targeted nanovectors as an effective strategy to deliver cytotoxic molecules to GSCs at the surgical tumor margins, the forefront of GBM recurrence, circumventing BBB hurdles. DOXO encapsulation proved in situ immune response activation within GBM microenvironment. |
| Databáze: | OpenAIRE |
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