Targeted and Synergic Glioblastoma Treatment: Multifunctional Nanoparticles Delivering Verteporfin as Adjuvant Therapy for Temozolomide Chemotherapy

Author(s)

Pellosi, Diogo S. ^{[1, 2]} ; Paula, Leonardo B. ^[2] ; de Melo, Maryanne T. ^[2] ; Tedesco, Antonio C. ^[2]

Affiliation

^[1] Univ Fed Sao Paulo, Dept Chem, Lab Hybrid Mat, BR-04021001 Diadema - Brazil

^[2] Univ Sao Paulo, Dept Chem, Photobiol & Photomed Res Grp, Ctr Nanotechnol & Tissue Engn, FFCLRP, Ribeirao Preto - Brazil

• Document type: Journal article
• Source: MOLECULAR PHARMACEUTICS; v. 16, n. 3, p. 1009-1024, MAR 2019.
• Web of Science Citations: 4

Abstract

Despite advances in cancer therapies, glioblastoma multiforme treatment remains inefficient due to the brain blood barrier (BBB) inhibitory activity and to the low temozolomide (TMZ) chemotherapeutic selectivity. To improve therapeutic outcomes, in this work we propose two strategies, (i) photodynamic therapy (PDT) as adjuvant treatment and (ii) engineering of multifunctional theranostic/targeted nanoparticles (m-NPs) that integrate biotin as a targeting moiety with rhodamine-B as a theranostic agent in pluronic P8S/F127 copolymers. These smart m-NPs can surmount the BBB and coencapsulate multiple cargoes under optimized conditions. Overall, the present study conducts a rational m-NP design, characterization, and optimizes the formulation conditions. Confocal microscopy studies on T98-G, U87-MG, and U343 glioblastoma cells and on NIH-3T3 normal fibroblast cells show that the m-NPs and the encapsulated drugs are selectively taken up by tumor cells presenting a broad intracellular distribution. The formulations display no toxicity in the absence of light and are not toxic to healthy cells, but they exert a robust synergic action in cancer cells in the case of concomitant PDT/TMZ treatment, especially at low TMZ concentrations and higher light doses, as demonstrated by nonlinear dose effect curves based on the Chou-Talalay method. The results evidenced different mechanisms of action related to the disjoint cell cycle phases at the optimal PDT/TMZ ratio. This effect favors synergism between the PDT and the chemotherapy with TMZ, enhances the antiproliferative effect, and overcomes cross-resistance mechanisms. These results point out that m-NP-based PDT adjuvant therapy is a promising strategy to improve TMZ-based glioblastoma multiforme treatments. (AU)

• FAPESP's process: 13/50181-1 - Use of drugs containing nanocarriers with photosensitizers and/or other active compounds applied to cell therapy and treatment of central nervous system disorders
• Grantee: Antonio Claudio Tedesco
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/00389-3 - MULTIFUNCTIONAL NANOPARTICLES FOR SITE-ESPECIFIC DELIVERY OF TEMOZOLOMIDE® AND VERTEPORFIN® FOR COMBINATION THERAPY OF BRAIN TUMORS
• Grantee: Diogo Silva Pellosi
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/24004-9 - Nanocarriers loaded with photosensitizers and others drugs derived of growth factors applied to Photodynamic Processes in treatment of central nervous system diseases
• Grantee: Leonardo Barcelos de Paula
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/18684-9 - Use of drugs containing nanocarriers with photosensitizers and/or other active compounds applied to cell therapy and treatment of central nervous system disorders
• Grantee: Leonardo Barcelos de Paula
• Support Opportunities: Scholarships in Brazil - Post-Doctoral