Selective Uptake Into Drug Resistant Mammalian Cancer by Cell Penetrating Peptide-Mediated Delivery

Abstract

Research over the past decade has identified several of the key limiting features of multidrug resistance (MDR) in cancer therapy applications, such as evolving glycoprotein receptors at the surface of the cell that limit therapeutic uptake, metabolic changes that lead to protection from multidrug resistant mediators which enhance degradation or efflux of therapeutics, and difficulty ensuring retention of intact and functional drugs once endocytosed. Nanoparticles have been demonstrated to be effective delivery vehicles for a plethora of therapeutic agents, and in the case of nucleic acid based agents, they provide protective advantages. Functionalizing cell penetrating peptides, also known as protein transduction domains, onto the surface of fluorescent quantum dots creates a labeled delivery package to investigate the nuances and difficulties of drug transport in MDR cancer cells for potential future clinical applications of diverse nanoparticle-based therapeutic delivery strategies. In this study, eight distinct cell penetrating peptides were used (CAAKA, HSV1-VP22, HIV-TAT, HIV-gp41, Ku-70, hCT(9-32), integrin-β3, and K-FGF) to examine the different cellular uptake profiles in cancer versus drug resistant melanoma (A375 & A375-R), mesothelioma (MSTO & MSTO-R), and glioma (rat 9L and 9L-R, and human U87 & LN18) cell lines. The results of this study demonstrate that cell penetrating peptide uptake varies with drug resistance status and cell type, likely due to changes in cell surface markers. This study provides insight into developing functional nanoplatform delivery systems in drug resistant cancer models.

Nanoparticles Modified with Cell-Penetrating Peptides: Conjugation Mechanisms, Physicochemical Properties, and Application in Cancer Diagnosis and Therapy

“…Generally, the attachment of CPPs to the NP surface has been shown to be beneficial for the accessibility of CPPs, which potentially enhances recognition of the peptide with the cell surface [76]. Nevertheless, the chemical interaction between functional groups of the peptide and those of the NPs can have a significant influence on the formation of the secondary structure.…”

“…Moreover, CPPs may be rationally modulated to target cancer cells [100]. Recently, Carnevale et al compared the uptake profiles of several different CPP-NPs in cancer cells versus cancer-resistant cells [76]. In fact, the authors used eight different CPPs, which were attached via bidentate coordination using the thiol and amine of cysteine to the NP surface to generate multi-shelled QDs, and tested their ability to enter cancer cells.…”

Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application

“…There are relatively few numbers of hydrophobic CPPs, and their structure contains a large number of non-polar residues or only a few charged amino acids (less than 20% of the sequence). Natural hydrophobic CPPs found so far include C105Y (Rhee and Davis, 2006), Bip4 (Gomez et al, 2010), and K-FGF (Carnevale et al, 2018). Different from what is known for most amphiphilic cationic CPPs, the peptide sequence of hydrophobic CPPs does not significantly affect cell uptake (Gomez et al, 2010).…”

Interdependence of charge and secondary structure on cellular uptake of cell penetrating peptide functionalized silica nanoparticles

“…8 Loading of CPPs onto nanoparticles has been shown to yield highly efficient carriers for anticancer drugs or diagnostic agents, 9 to increase the target availability to cell surfaces, and to potentially enhance peptide recognition. 10 While most studies on nanoparticle-CPP interactions focused on the use of polymeric, micellar or lipid nanoparticles, relatively few reports are available on the use of inorganic carriers such as gold, 11,12 quantum dots 10,13,14 or magnetic nanostructures. 15 A variety of functionalization strategies including streptavidin-biotin conjugation, 13 linkages via polyethylene glycol 11 or cysteine-based cross-linking 10,12,14,16 were successfully demonstrated to synthesize nanocarriers.…”

“…10 While most studies on nanoparticle-CPP interactions focused on the use of polymeric, micellar or lipid nanoparticles, relatively few reports are available on the use of inorganic carriers such as gold, 11,12 quantum dots 10,13,14 or magnetic nanostructures. 15 A variety of functionalization strategies including streptavidin-biotin conjugation, 13 linkages via polyethylene glycol 11 or cysteine-based cross-linking 10,12,14,16 were successfully demonstrated to synthesize nanocarriers. However, since covalent linkages can signicantly alter the native structure and thus the functionality of the conjugated biomolecule, 5 non-covalent approaches via electrostatic interactions represent a valuable, biologically relevant and simple alternative.…”