Cell penetrating elastin-like polypeptides for therapeutic peptide delivery

University of Mississippi Medical Center, Department of Biochemistry, Jackson, 39216, USA.
Advanced drug delivery reviews (Impact Factor: 15.04). 12/2010; 62(15):1486-96. DOI: 10.1016/j.addr.2010.05.003
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Current treatment of solid tumors is limited by side effects that result from the non-specific delivery of drugs to the tumor site. Alternative targeted therapeutic approaches for localized tumors would significantly reduce systemic toxicity. Peptide therapeutics are a promising new strategy for targeted cancer therapy because of the ease of peptide design and the specificity of peptides for their intracellular molecular targets. However, the utility of peptides is limited by their poor pharmacokinetic parameters and poor tissue and cellular membrane permeability in vivo. This review article summarizes the development of elastin-like polypeptide (ELP) as a potential carrier for thermally targeted delivery of therapeutic peptides (TP), and the use of cell penetrating peptides (CPP) to enhance the intracellular delivery of the ELP-fused TPs. CPP-fused ELPs have been used to deliver a peptide inhibitor of c-Myc function and a peptide mimetic of p21 in several cancer models in vitro, and both polypeptides are currently yielding promising results in in vivo models of breast and brain cancer.

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    • "W. Urry et al., 1991). Two versions of ELP were tested in this study, one with 160 VPGxG repeats, a molecular weight of about 61 kDa, and a transition temperature of 65 °C, and a second with the same ELP modified at the N-terminus by the addition of a cell penetrating peptide (CPP) called SynB1 (Bidwell et al., 2010; Rousselle et al., 2001). We have shown previously that the addition of a CPP to ELP enhances its cellular uptake in vitro (Bidwell and Raucher, 2005; Bidwell et al., 2009, 2007; Massodi et al., 2010, 2005) and influences its biodistribution in vivo (Bidwell et al., 2013, 2012; Moktan et al., 2012). "
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    ABSTRACT: Abstract Background: Pregnant females are largely overlooked in drug development due to concerns for fetal health. Additionally, pregnancy is often an exclusion criterion in clinical trials, so the safety of many drugs during pregnancy is unknown. Purpose: The goal of this study was to evaluate Elastin-like Polypeptide (ELP), a synthetic protein derived from human elastin, for maternally sequestered drug delivery. ELP is a versatile drug carrier with a long plasma half-life, low immunogenicity, and the ability to be fused to nearly any small molecule or protein-based therapeutic. Methods: We determined the pharmacokinetics, biodistribution, and fetal exposure to the ELP drug carrier using quantitative fluorescence techniques in a rat pregnancy model. Results: After either bolus IV administration or continuous infusion over five days, ELPs accumulated strongly in the kidneys, liver, and placenta, but importantly, little to no ELPs were detectable in the fetus. Within the placenta, ELPs were localized to the chorionic plate and broadly distributed within the labyrinth, but were excluded from the fetal portion of the chorionic villi. Conclusion: These data indicate that ELP does not cross the placenta, and they suggest that this adaptable drug delivery system is a promising platform for prevention of fetal drug exposure.
    Journal of Drug Targeting 08/2014; 22(10):1-13. DOI:10.3109/1061186X.2014.950666 · 2.74 Impact Factor
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    • "These polymers possess several advantages compared to other anticancer drug delivery vehicles that appeared to be complementary and synergistic with existing technologies: (1) composition of ELPs can be precisely encoded at the gene level, (2) ELPs have the advantages and characteristics of soluble macromolecules which accumulate in tumors due to a passive targeting provided by enhanced permeability and retention effect, (3) they are thermally responsive and may be actively targeted by application of local hyperthermia,(4) the addition of CPPs to the ELP chain enhances uptake into the tumor cells, and moreover, CPPs also mediate the escape of polymers from the tumor vasculature into the tumor cells. (5) the addition of CPPs can target ELP to the desired cellular compartment (Bidwell III and Raucher 2010), (6) peptide-based biomaterials are easily degraded by the body and possess good biocompatibility, (7) ELP half-life in the plasma can be precisely controlled. "
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    ABSTRACT: Elastin-like polypeptides (ELP) are artificial, genetically encodable biopolymers, belonging to elastomeric proteins, which are widespread in a wide range of living organisms. They are composed of a repeating pentapeptide sequence Val-Pro-Gly-Xaa-Gly, where the guest residue (Xaa) can be any naturally occurring amino acid except proline. These polymers undergo reversible phase transition that can be triggered by various environmental stimuli, such as temperature, pH or ionic strength. This behavior depends greatly on the molecular weight, concentration of ELP in the solution and composition of the amino acids constituting ELPs. At a temperature below the inverse transition temperature (Tt), ELPs are soluble, but insoluble when the temperature exceeds Tt. Furthermore, this feature is retained even when ELP is fused to the protein of interest. These unique properties make ELP very useful for a wide variety of biomedical applications (e.g. protein purification, drug delivery etc.) and it can be expected that smart biopolymers will play a significant role in the development of most new materials and technologies. Here we present the structure and properties of thermally responsive elastin-like polypeptides with a particular emphasis on biomedical and biotechnological application.
    World Journal of Microbiology and Biotechnology (Formerly MIRCEN Journal of Applied Microbiology and Biotechnology) 04/2014; 30(8). DOI:10.1007/s11274-014-1649-5 · 1.78 Impact Factor
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    • "ELPs enter the cell by endocytosis (caveolae-independent mechanism) (Bidwell III and Raucher, 2010) and when conjugated with CPPs (e.g. TAT peptide, penetratin or membrane translocating sequence (MTS) peptide), the internalization is highly effective – for example, Penetratin-ELP induced a 13-fold cellular uptake increase due to aggregation of the polypeptide at the tumor site; this conjugation improved target delivery by interacting with specific receptors or proteins that are overexpressed at the cell surface (Bidwell III and Raucher, 2010). The attachment of an active ligand demonstrated promising results in multivalent micelles for targeted anticancer therapy (Callahan and Chilkoti, 2010). "
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    ABSTRACT: This chapter reviews the most significant discovers in biomaterial-based systems for drug delivery in the last decades. Biomaterials have been explored as drug delivery systems in medicine since the mid-1960’s and, almost half a century later, incessant advances in basic sciences, engineering, medicine and pharmaceutical sciences led to the development of new biomaterials and improvement of the existing ones. Many materials, much as lipids, proteins, polysaccharides and also polyester polymers are successfully used as encapsulation materials. Recent works focus their attention on the arrangement of different biomacromolecules and biomaterials for enhancing the properties of the drug delivery systems. Advantages in controlled drug release, targeting delivery and more flexibility and in vivo stability have been demonstrated with these new materials. Finally, adaptation of “smart” materials to the biological conditions and modification of cells and lipid bilayers interactions also increased the drug nanocarriers’ applications in medical field.
    Biomaterials of Nanotechnology, Edited by J.N. Govil, 01/2014: chapter 5: pages 484; Studium Press LLC., ISBN: 1-626990-11-5
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