ear-Infrared Fluorescent Micelles from Poly(norbornene) Brush Triblock Copolymers for Nanotheranostic

Autor(es)

Braga, Carolyne B. ^{[1, 2, 3]} ; Pilli, Ronaldo A. ^[1] ; Ornelas, Catia ^[1] ; Weck, Marcus ^{[2, 3]}

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Inst Chem, UNICAMP, BR-13083970 Campinas, SP - Brazil

^[2] NYU, Dept Chem, New York, NY 10003 - USA

^[3] NYU, Mol Design Inst, New York, NY 10003 - USA

• Tipo de documento: Artigo Científico
• Fonte: Biomacromolecules; v. 22, n. 12, p. 5290-5306, DEC 13 2021.
• Citações Web of Science: 0

Resumo

This contribution describes the design and synthesis of multifunctional micelles based on amphiphilic brush block copolymers (BBCPs) for imaging and selective drug delivery of natural anticancer compounds. Well-defined BBCPs were synthesized via one-pot multi-step sequential grafting-through ring-opening metathesis polymerization (ROMP) of norbornene-based macroinitiators. The norbornenes employed contain a poly(ethylene glycol) methyl ether chain, an alkyl bromide chain, and/or a near-infrared (NIR) fluorescent cyanine dye. After block copolymerization, post-polymerization transformations using bromide-azide substitution, followed by the strain-promoted azide-alkyne cycloaddition (SPAAC) allowed for the functionalization of the BBCPs with the piplartine (PPT) moiety, a natural product with well-documented cytotoxicity against cancer cell lines, via an ester linker between the drug and the polymer side chain. The amphiphilic BBCPs self-assembled in aqueous media into nano-sized spherical micelles with neutral surface charges, as confirmed by dynamic light scattering analysis and transmission electron microscopy. During self-assembly, paclitaxel (PTX) could be effectively encapsulated into the hydrophobic core to form stable PTX-loaded micelles with high loading capacities and encapsulation efficiencies. The NIR fluorescent dye-containing micelles exhibited remarkable photophysical properties, excellent colloidal stability under physiological conditions, and a pH-induced disassembly under slightly acidic conditions, allowing for the release of the drug in a controlled manner. The in vitro studies demonstrated that the micelles without the drug (blank micelles) are biocompatible at concentrations of up to 1 mg mL(-1) and present a high cellular internalization capacity toward MCF-7 cancer cells. The drug-functionalized micelles showed in vitro cytotoxicity comparable to free PPT and PTX against MCF-7 and PC3 cancer cells, confirming efficient drug release into the tumor environment upon cellular internalization. Furthermore, the drug-functionalized micelles exhibited higher selectivity than the pristine drugs and preferential cellular uptake in human cancer cell lines (MCF-7 and PC3) when compared to the normal breast cell line (MCF10A). This study provides an efficient strategy for the development of versatile polymeric nanosystems for drug delivery and image-guided diagnostics. Notably, the easy functionalization of BBCP side chains via SPAAC opens up the possibility for the preparation of a library of multifunctional systems containing other drugs or functionalities, such as target groups for recognition. (AU)

• Processo FAPESP: 13/07607-8 - CMPO - Centro Multidisciplinar de Pesquisa em Obesidade e Doenças Associadas
• Beneficiário: Licio Augusto Velloso
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 19/13104-5 - Planejamento e síntese de inibidores baseado em alvo biológico: o caso das quinases negligenciadas
• Beneficiário: Ronaldo Aloise Pilli
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 08/57906-3 - Instituto Nacional de Fotônica Aplicada à Biologia Celular - INFABIC
• Beneficiário: Hernandes Faustino de Carvalho
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 14/50906-9 - INCT 2014: em Materiais Complexos Funcionais (INOMAT)
• Beneficiário: Fernando Galembeck
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/24020-4 - Conjugados polinorborneno-goniotalamina e polinorborneno-piplartina para terapias anticâncer
• Beneficiário: Carolyne Brustolin Braga
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
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• Beneficiário: Carolyne Brustolin Braga
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado