Accumulation of arginine-rich cell-penetrating peptides in tumors and the potential for anticancer drug delivery in vivo.
ABSTRACT We investigated the biodistribution of arginine-rich cell-penetrating peptides (CPPs) in tumor-xenografted nude mice after intravenous injection of fluorescently labeled CPPs using in vivo imaging. The CPPs used included HIV-1 Tat (48-60), penetratin, and the L- and D-enantiomers of oligoarginines (8, 12, and 16 residues), all of which are reported to have high cell penetration. Among the tested peptides, high accumulation in tumors was observed for the D-form of octaarginine (r8), and glycosaminoglycans played a key role. Injection of an r8-doxorubicin conjugate (4mg doxorubicin/kg) effectively suppressed tumor proliferation, with no significant decrease in mouse weight, whereas administration of doxorubicin itself (6mg/kg), yielding a similar degree of tumor-growth suppression, resulted in significant weight loss. These results suggest the potential of r8 as a prototypic tumor-targeting vector.
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ABSTRACT: Cell-penetrating peptides (CPPs) comprised of basic amino residues are able to cross cytoplasmic membranes and are able to deliver biologically active molecules inside cells. However, CPP/cargo entrapment in endosome limits biomedical utility as cargoes are destroyed in the acidic environment. In this study, we demonstrate protein transduction of a novel CPP comprised of an INF7 fusion peptide and nona-arginine (designated IR9). IR9 noncovalently interacts with quantum dots (QDs) and DNAs to form stable IR9/QD and IR9/DNA complexes which are capable of entering human A549 cells. Zeta-potentials were a better predictor of transduction efficiency than gel shift analysis, emphasizing the importance of electrostatic interactions of CPP/cargo complexes with plasma membranes. Mechanistic studies revealed that IR9, IR9/QD and IR9/DNA complexes may enter cells by endocytosis. Further, IR9, IR9/QD and IR9/DNA complexes were not cytotoxic at concentrations below 30, 5 and 20.1 µM, respectively. Without labor intensive production of fusion proteins from prokaryotes, these results indicate that IR9 could be a safe carrier of genes and drugs in biomedical applications.PLoS ONE 01/2013; 8(5):e64205. · 3.73 Impact Factor
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ABSTRACT: Block copolymer micelles have shown great potential in drug delivery systems, not only for overcoming the drawbacks of small agents such as water insolubility and wide distribution in normal tissues, but also for avoiding traditional nanoparticle formulation shortcomings, including in vivo instability and fast clearance from the blood. However, for translating micellar formulations to clinical practice, it is essential to overcome the many in vivo obstacles. Surmounting these barriers strongly depends on micellar physicochemical properties, which can be further optimized by the unique physiological aspects of solid tumors such as low pH, high temperature and the presence of abnormal vessels. Herein, based on the Flory parameter and scaling theory, the fundamental mechanisms and correlations in vitro/in vivo between self assembly, drug loading and release, stability, intracellular delivery and in vivo distribution, as well as micellar composition, size and microstructural tailoring are systematically revisited. The methods for enhancing micellar performance in solid tumors were consequently proposed through well-defined core-corona structure tailoring.Nanomedicine 08/2012; 7(8):1235-52. · 5.26 Impact Factor
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ABSTRACT: Co-culture models are currently bridging the gap between classical cultures and in vivo animal models. Exploring this novel approach unlocks the possibility to mimic the tumor microenvironment in vitro, though the establishment of cancer-stroma synergistic interactions. Notably, these organotypic models offer a perfect platform for the development and pre-clinical evaluation of candidate nanocarriers loaded with antitumoral drugs in a high throughput screening mode, with lower costs and absence of ethical issues. However, this evaluation was until now limited to co-culture systems established with precise cell ratios, not addressing the natural cell heterogeneity commonly found in different tumors. Therefore, herein the multifunctional nanocarriers efficiency was characterized in various fibroblast-MCF-7 co-culture systems containing different cell ratios, in order to unravel key design parameters that influence nanocarrier performance and the therapeutic outcome. The successful establishment of the co-culture models was confirmed by the tissue-like distribution of the different cells in culture. Nanoparticle incubation in the various co-culture systems reveals that these nanocarriers possess targeting specificity for cancer cells, indicating their suitability for being used in this illness therapy. Additionally, by using different coculture ratios, different nanoparticle uptake profiles were obtained. These findings are of crucial importance for the future design and optimization of new drug delivery systems since their real targeting capacity must be addressed in heterogenous cell populations, such as those found in tumors.PLoS ONE 07/2013; · 3.73 Impact Factor