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Nanotheranostics 2021; 5(2):213-239. doi:10.7150/ntno.54491 This issue Cite

Research Paper

Nanotheranostics through Mitochondria-targeted Delivery with Fluorescent Peptidomimetic Nanohybrids for Apoptosis Induction of Brain Cancer Cells

Isadora C. Carvalho, Alexandra A. P. Mansur, Sandhra M. Carvalho, Herman S. Mansur^✉

Center of Nanoscience, Nanotechnology, and Innovation - CeNano²I, Department of Metallurgical and Materials Engineering, Federal University of Minas Gerais - UFMG, Av. Antônio Carlos, 6627 - Belo Horizonte/MG, Brazil.

✉ Corresponding author: Federal University of Minas Gerais, Av. Antônio Carlos, 6627 - Escola de Engenharia, Bloco 2 - Sala 2233, 31.270-901, Belo Horizonte/ MG, Brazil; Phone: +55-31-34091843; E-mail: hmansurufmg.br (H. Mansur)

Abstract

Overview: Malignant brain tumors remain one of the greatest challenges faced by health professionals and scientists among the utmost lethal forms of cancer. Nanotheranostics can play a pivotal role in developing revolutionary nanoarchitectures with multifunctional and multimodal capabilities to fight cancer. Mitochondria are vital organelles to eukaryotic cells, which have been recognized as a significant target in cancer therapy where, by damaging the mitochondria, it will cause irreparable cell death or apoptosis.

Methods: We designed and produced novel hybrid nanostructures comprising a fluorescent semiconductor core (AgInS₂, AIS) and cysteine-modified carboxymethylcellulose (termed thiomer, CMC_Cys) conjugated with mitochondria-targeting peptides (KLA) forming a macromolecular shell for combining bioimaging and for inducing brain cancer cell (U-87 MG) death.

Results: The optical and physicochemical properties of the nanoconjugates demonstrated suitability as photoluminescent nanostructures for cell bioimaging and intracellular tracking. Additionally, the results proved a remarkable killing activity towards glioblastoma cells of cysteine-bearing CMC conjugates coupled with KLA peptides through the half-maximal effective concentration values, approximately 70-fold higher compared to the conjugate analogs without Cys residues. Moreover, these thiomer-based pro-apoptotic drug nanoconjugates displayed higher lethality against U-87 MG cancer cells than doxorubicin, a model drug in chemotherapy, although extremely toxic. Remarkably, these peptidomimetic nanohybrids demonstrated a relative “protective effect” regarding healthy cells while maintaining high killing activity towards malignant brain cells.

Conclusion: These findings pave the way for developing hybrid nanoarchitectures applied as targeted multifunctional platforms for simultaneous imaging and therapy against cancer while minimizing the high systemic toxicity and side-effects of conventional drugs in anticancer chemotherapy.

Keywords: nanoconjugates, fluorescent nanoparticles, dual-functional bioconjugates, cancer nanomedicine, dual-targeted drug delivery

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