Drug delivery to solid tumors by elastin-like polypeptides

Abstract

Thermally responsive elastin-like polypeptides (ELPs) are a promising class of recombinant biopolymers for the delivery of drugs and imaging agents to solid tumors via systemic or local administration. This article reviews four applications of ELPs to drug delivery, with each delivery mechanism designed to best exploit the relationship between the characteristic transition temperature (T t ) of the ELP and body temperature (T b ). First, when T t >> T b , small hydrophobic drugs can be conjugated to the C-terminus of the ELP to impart the amphiphilicity needed to mediate the self-assembly of nanoparticles. These systemically delivered ELP-drug nanoparticles preferentially localize to the tumor site via the EPR effect, resulting in reduced toxicity and enhanced treatment efficacy. The remaining three approaches take direct advantage of the thermal responsiveness of ELPs. In the second strategy, where T b < T t < 42 °C, an ELP-drug conjugate can be injected in conjunction with external application of mild hyperthermia to the tumor to induce ELP coacervation and an increase in concentration within the tumor vasculature. The third approach utilizes hydrophilic-hydrophobic ELP block copolymers that have been designed to assemble into nanoparticles in response to hyperthermai due to the independent thermal transition of the hydrophobic block, thus resulting in multivalent ligand display of a ligand for spatially enhanced vascular targeting. In the final strategy, ELPs with T t < T b are conjugated with radiotherapeutics, injtect intioa tumor where they undergo coacervation to form an injectable drug depot for intratumoral delivery. These injectable coacervate ELP-radionuclide depots display a long residence in the tumor and result in inhibition of tumor growth.

Peptide-Based Polymer Therapeutics

“…Cell experiments showed higher cytotoxicity combining heat and K8-ELP-GA [105]. Chilkoti et al have reviewed multiple alternatives for these systems [106,107]. ELPs have been successfully fused to a peptide (H1) inhibitor of an oncogene [108] together with penetratin (Pen) in order to allow membrane translocation demonstrating that Pen-ELP-H1 inhibits cell growth and more importantly, that hyperthermia significantly enhances treatment effectiveness.…”

Rational design of fiber forming supramolecular structures

“…25 The reader is directed to the following reviews for more details. 29,[149][150][151] These synthetic elastin matrices, oftentimes combined with synthetic collagen matrices, have been used to recapitulate features of the ECM in applications for tissue repair, [152][153][154][155][156] drug delivery, 29,157,158 and materials with tunable material properties. 150,154,[159][160][161] …”

Elastin-like polypeptides and their applications in anticancer drug delivery systems: a review

“…Biocompatibility, biodegradability and non immunogenic properties of ELPs suggest their suitability for in vivo applications (Mackay & Chilkoti, 2008). ELPs have molecular weight greater than the renal threshold and can be retained for significantly long periods of time in blood circulation, thus increasing their plasma half-lives (Liu et al, 2006;McDaniel et al, 2010). They are degradable by proteolysis which reduces their adverse side effect due to long-term accumulation in the body (Mackay & Chilkoti, 2008).…”