A Hybrid Protein–Polymer Nanoworm Potentiates Apoptosis Better than a Monoclonal Antibody

127

104

Elastin-like polypeptides (ELPs) constitute a genetically engineered class of ‘protein polymers’ derived from human tropoelastin. They exhibit a reversible phase separation whereby samples remain soluble below a transition temperature (Tt) but form amorphous coacervates above Tt. Their phase behavior has many possible applications in purification, sensing, activation, and nanoassembly. As humanized polypeptides, they are non-immunogenic, substrates for proteolytic biodegradation, and can be decorated with pharmacologically active peptides, proteins, and small molecules. Recombinant synthesis additionally allows precise control over ELP architecture and molecular weight, resulting in protein polymers with uniform physicochemical properties suited to the design of multifunctional biologics. As such, ELPs have been employed for various uses including as anti-cancer agents, ocular drug delivery vehicles, and protein trafficking modulators. This review aims to offer the reader a catalogue of ELPs, their various applications, and potential for commercialization across a broad spectrum of fields.

Section: Applicationssupporting

confidence: 55%

“…To address these shortcomings, many investigators have turned to bioconjugation with high molecular weight polymers as a means of prolonging scFv half-lives[118]. Applying those findings to ELPs, anti-CD20 scFv was generated through fusion to the ~73 kDa A192 monomer by Aluri and coworkers[119]. …”

Section: Applicationsmentioning

confidence: 99%

Elastin-like polypeptides: Therapeutic applications for an emerging class of nanomedicines

Despanie

Dhandhukia

Hamm‐Alvarez

et al. 2016

127

104

“…Second, the morphologies of ELPs exploited for drug delivery will realize a growing diversity as we obtain a greater understanding of the parameters that can drive ELP self-assembly. Structures such as vesicles [120], nanofibers [121], and nanoworms [122] have already been observed with vehicle systems containing an ELP component. Advances in the de novo design of such morphologies by experimental determination—or alternatively, theoretical prediction—of the phase diagrams of these systems is critical because it will allow the a priori design, at the amino acid sequence level, of drug carriers with tunable sizes and morphologies.…”

Section: Conclusion Future Directions and Challengesmentioning

confidence: 99%

Applications of elastin-like polypeptides in drug delivery

MacEwan

Chilkoti

2014

208

236

Elastin-like polypeptides (ELPs) are biopolymers inspired by human elastin. Their lower critical solution temperature phase transition behavior and biocompatibility make them useful materials for stimulus-responsive applications in biological environments. Due to their genetically encoded design and recombinant synthesis, the sequence and size of ELPs can be exactly defined. These design parameters control the structure and function of the ELP with a precision that is unmatched by synthetic polymers. Due to these attributes, ELPs have been used extensively for drug delivery in a variety of different embodiments—as soluble macromolecular carriers, self-assembled nanoparticles, cross-linked microparticles, or thermally coacervated depots. These ELP systems have been used to deliver biologic therapeutics, radionuclides, and small molecule drugs to a variety of anatomical sites for the treatment of diseases including cancer, type 2 diabetes, osteoarthritis, and neuroinflammation.

“…ELPs are soluble in aqueous solutions below their transition temperature ( T t ) and self-assemble into various-sized particles above T t [27]. T t can be precisely modulated by adjusting the number of pentapeptide repeats, n, and the hydrophobicity of the guest residue, X, which can determine whether the ELP remains a soluble macromolecular drug carrier [28], assembles a nanoparticle [29], or phase separates into micron-sized coacervates [30] at physiological temperature. With their distinctive thermo-responsive, elastic, and biocompatible properties, ELPs have impacted fields such as protein purification [31], stimuli responsive hydrogels [32], tissue engineering [33, 34], and targeted cancer treatment [35, 36].…”

Section: Introductionmentioning

confidence: 99%

A thermo-responsive protein treatment for dry eyes

Wang

Jashnani

Aluri

et al. 2015

Self Cite

Millions of Americans suffer from dry eye disease, and there are few effective therapies capable of treating these patients. A decade ago, an abundant protein component of human tears was discovered and named lacritin(Lacrt). Lacrt has prosecretory activity in the lacrimal gland and mitogenic activity at the corneal epithelium. Similar to other proteins placed on the ocular surface, the durability of its effect is limited by rapid tear turnover. Motivated by the rationale that a thermo-responsive coacervate containing Lacrt would have better retention upon administration, we have constructed and tested the activity of a thermo-responsive Lacrt fused to an Elastin-like polypeptide (ELP). Inspired from the human tropoelastin protein, ELP protein polymers reversibly phase separate into viscous coacervates above a tunable transition temperature. This fusion construct exhibited the prosecretory function of native Lacrt as illustrated by its ability to stimulate β-hexosaminidase secretion from primary rabbit lacrimal gland acinar cells. It also increased tear secretion from non-obese diabetic (NOD) mice, a model of autoimmune dacryoadenitis, when administered via intra-lacrimal injection. Lacrt ELP fusion proteins undergo temperature-mediated assembly to form a depot inside the lacrimal gland. We propose that these Lacrt ELP fusion proteins represent a potential therapy for dry eye disease and the strategy of ELP-mediated phase separation may have applicability to other diseases of the ocular surface.