Dados do Trabalho

Título

Collagen-binding thermosensitive nanoparticles for breast cancer treatment

Introdução

Ductal carcinoma in situ (DCIS) is a local form of breast cancer, but its treatment is aggressive due to the risk of progression to invasive cancer. Since DCIS develops within the ducts, intraductal drug delivery can maximize local drug concentration and minimize systemic adverse effects. In this study, we developed a novel hybrid thermosensitive collagen-binding nanoparticle for paclitaxel intraductal administration and local breast cancer treatment.

Objetivo

The aim of this study was to develop and evaluate hybrid thermosensitive nanoparticles, consisting of a nanostructured lipid carrier (NLC) core with a poly(N-isopropylacrylamide) shell. The particles were functionalized with SILY, a peptide that binds to collagen type I, aiming to increase selectivity and prolong treatment tissue retention.

Métodos

NLC were obtained using Compritol and tributyrin as lipids. To obtain hybrid particles, the NLC (“cores”) were encapsulated within a shell of pNIPAM using a precipitation polymerization reaction; polymeric-only particles were produced for comparison. Nanoparticles were characterized using flow cytometry, light scattering, transmission electron microscopy, and paclitaxel encapsulation and release. To improve selectivity and breast tissue retention, nanoparticles were functionalized with various (50 – 400%) ratios of the peptide (RRANAALKAGELYKSILYGC, abbreviated SILY), and their collagen-binding ability was evaluated in collagen-coated plates and collagen secreted by breast tumor cells (MCF-7 and T-47D). The selectivity and cytotoxicity of the nanoparticles were investigated in a co-culture model, in which breast cancer cells were cultured in transwell inserts placed in plates containing non-tumor (MCF-10A) cells. Cells in the inserts were treated with the particles, and viability in both compartments was assessed using MTS.

Resultados

Compared to the NLC, coating with pNIPAM increased particle size by approximately 140 nm (380.4 ± 4.4 nm). The hybrid nanoparticles exhibited high loading efficiency (<76%), which was 1.2-fold higher than the polymeric particle, and sustained paclitaxel release for up to 5 days. Hybrid nanoparticles' thermal responsiveness was maintained, which may contribute to paclitaxel controlled release; at physiological temperature nanoparticles’ size decreased by 1.64-fold. SILY modification increased collagen binding; nanoparticles successfully bound to collagen-coated surfaces and collagen synthesized by breast tumor cells. NLC showed the greatest ability to reduce MCF-7 and T-47D spheroids viability (IC50 5.0 – 6.9 mg/mL), followed by hybrid (7.7 – 10.0 mg/mL) and pNIPAM nanoparticles (11.4 – 17.9 mg/mL). Encapsulation of paclitaxel did not increase its cytotoxicity compared to its solution. In the co-culture model, functionalization of nanoparticles with SILY resulted in higher viability of non-tumor cells cultured in the plates, suggesting that functionalization increased selectivity.

Conclusões

Encapsulation of lipid cores in pNIPAM shells increased functionalization with SILY. Hybrid particles sustained paclitaxel release and showed greater cytotoxicity in tumor cells compared to pNIPAM-only particles while increasing selectivity towards cancer cells. The study provides a promising system for DCIS therapy, highlighting the possibility of a local treatment.

Palavras-chave

breast cancer, core-shell nanoparticles, collagen binding peptide

Financiador do resumo

FAPESP, grants #2020/01208-8 and #2021/12664-7 and CAPES – Brazilian Federal Agency for Support and Evaluation of Graduate Education within the Ministry of Education of Brazil (finance code 001).