Abstract
The delivery of Cytochrome c (Cyt c) to the cytosol stimulates apoptosis in cells where its release from mitochondria and apoptotic induction is inhibited. We developed a drug delivery system consisting of Cyt c nanoparticles decorated with folate-poly(ethylene glycol)-poly(lactic-co-glycolic acid)-thiol (FA-PEG-PLGA-SH) to deliver Cyt c into cancer cells and tested their targeting in the Lewis Lung Carcinoma (LLC) mouse model. Cyt c-PLGA-PEG-FA nanoparticles (NPs) of 253 ± 55 and 354 ± 11 nm were obtained by Cyt c nanoprecipitation, followed by surface decoration with the co-polymer SH-PLGA-PEG-FA. The internalization of Cyt c-PLGA-PEG-FA nanoparticles (NPs) in LLC cells was confirmed by confocal microscopy. NP caspase activation was more efficient than the NP-free formulation. Caspase activity assays showed NPs retained 88–96% Cyt c activity. The NP formulations were more effective in decreasing LLC cell viability than NP-free formulation, with IC50 49.2 to 70.1 μg/mL versus 129.5 μg/mL, respectively. Our NP system proved to be thrice as selective towards cancerous than normal cells. In vivo studies using near infrared-tagged nanoparticles show accumulation in mouse LLC tumor 5 min post-injection. In conclusion, our NP delivery system for Cyt c shows superiority over the NP-free formulation and reaches a folic acid-overexpressing tumor in an immune-competent animal model.
Highlights
Apoptosis evasion is one of the hallmarks in all cancer types [1]
We addressed this challenge by adding a Folic acid (FA) ligand in the surface of the NP to induce FA receptor-mediated endocytosis
To confirm if Lewis Lung Carcinoma (LLC) cells could carry out this process, we studied the FA internalization kinetics by confocal microscopy
Summary
Apoptosis evasion is one of the hallmarks in all cancer types [1]. The mitochondrial apoptosis pathway has been extensively studied and is known to be the most commonly hindered apoptotic pathway in cancer cells. Our group and others have developed several drug delivery systems for Cyt c, which can induce apoptosis selectively in different cancer types by targeting the mitochondrial apoptotic pathway [11,12,13,14,15,16,17]. These systems were designed to release the drugs under reducing conditions like the ones found in the cellular cytosol, but not outside the cell, increasing their effective dose and lowering off-targets and premature drug release [18]
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