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

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.

Intermolecular Electrostatic Interactions in Cytochrome c Protein Monolayer on Montmorillonite Alumosilicate Surface: A Positive Cooperative Effect

“…Most authors reported maximal cytotoxicity, which does not exceed 60-80% using various sophisticated artificial nanoparticles bearing cytC, including solid-state dielectric as silica [63,65], hybrid gold-silica [66] and gold-ferric oxide even when cytC is combined with anticancer chemotherapeutics [67,68]. Higher cytotoxicity (up to 90%) is reached by using colloid particles prepared with cytC [69,70]. We achieved 97% cytotoxicity (ratio of dead to alive cells) in the 96th hour after addition of a suspension of the cytC-MM hybrid particles to a colon cancer cell culture [9,71] using montmorillonite colloid particles as a carrier of native cytC globules.…”

Cationic dextrin nanoparticles for effective intracellular delivery of cytochrome C in cancer therapy

“…20 However, a major challenge associated with nanocarrier systems is achieving a high protein loading efficiency with simultaneous release of protein at the target site in its active form. 21 Many researchers have devised methods for effective cargo protein encapsulation employing various kinds of nanocarriers, including liposomes, 22 synthetic polymers, 23 natural polymers, polymeric micelles 14 and mesoporous silica nanoparticles, in order to best achieve this aim. 1,[24][25][26] It is anticipated that among these, NPs generated from naturally occurring polysaccharides will find a way towards clinical usage in the treatment of cancer due to their outstanding biocompatibility and low immunogenicity.…”