Folate-Decorated Cross-Linked Cytochrome c Nanoparticles for Active Targeting of Non-Small Cell Lung Carcinoma (NSCLC).

Irivette Dominguez-Martinez,Kai H Griebenow,Freisa Joaquin-Ovalle,Yancy Ferrer-Acosta

doi:10.3390/pharmaceutics14030490

Irivette Dominguez-Martinez, Kai H Griebenow + Show 2 more

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https://doi.org/10.3390/pharmaceutics14030490

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Abstract

The folate receptor alpha (FR), which is overexpressed in solid tumors including NSCLC, can be utilized for active tumor targeting to afford more effective cancer therapies. In this context, cytochrome c (Cyt c) has drawn attention to cancer research because it is non-toxic, yet, when delivered to the cytoplasm of cancer cells, can kill them by inducing apoptosis. Cyt c nanoparticles (NPs, 169 ± 9 nm) were obtained by solvent precipitation with acetonitrile, and stabilized by reversible homo-bifunctional crosslinking to accomplish a Cyt-c-based drug delivery system that combines stimulus-responsive release and active targeting. Cyt c was released under intracellular redox conditions, due to an S–S bond in the NPs linker, while NPs remained intact without any release under extracellular conditions. The NP surface was decorated with a hydrophilic folic acid–polyethylene glycol (FA–PEG) polymer for active targeting. The FA-decorated NPs specifically recognized and killed cancer cells (IC50 = 47.46 µg/mL) that overexpressed FR, but showed no toxicity against FR-negative cells. Confocal microscopy confirmed the preferential uptake and apoptosis induction of our NPs by FR-positive cancer cells. In vivo experiments using a Lewis lung carcinoma (LLC) mouse model showed visible NP accumulation within the tumor and inhibited the growth of LLC tumors.

Highlights

Lung cancer is the leading cause of worldwide cancer deaths
Our results showed that colocalization of DAPI and propidium iodide (PI) occurred in Lewis lung carcinoma (LLC) cells, indicating ongoing late apoptosis, whereas NIH/3T3 cells showed no indication of dye colocalization
We report the development of a crosslinked cytochrome c (Cyt c)–polyethylene glycol (PEG)–Folic acid (FA) NP

Summary

Introduction

Lung cancer is the leading cause of worldwide cancer deaths. Non-small cell lung carcinoma (NSCLC) is the most common type of lung cancer, accounting for 85% of the reported cases, and is associated with poor prognosis—a five-year survival rate of only15% [1,2]. Against NSCLC have been successful to some extent, their main drawbacks are their non-specific targeting, high dose requirements, poor bioavailability, the development of multiple drug resistance, and adverse side effects [3,4,5]. NSCLC patients treated with cisplatin often suffer severe nephrotoxicity [6]. In principle, these effects arise from the chemotherapeutic agents’ lack of tumor selectivity and systemic toxicity without discriminating healthy tissues, producing unwanted and often severe and dangerous side effects. Regardless of their specific target or mechanism of action, produce the same cytotoxic end effect in sensitive cells: cell death.

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