Switchable Elastin-Like Polypeptides that Respond to Chemical Inducers of Dimerization

Dhandhukia, Jugal; Weitzhandler, Isaac; Wang, Wan; MacKay, J. Andrew

doi:10.1021/bm301558q

Cited by 27 publications

(33 citation statements)

References 40 publications

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“…Consistent with previous reports [27, 28, 36], optical density was measured at 350 nm as a function of temperature, a wavelength at which LV96 and V96 contribute little absorption. ELPs (5 to 100 μM) were observed in PBS under a temperature gradient of 1 °C/min (10 to 45 °C).…”

Section: Methodssupporting

confidence: 91%

“…One unique property of ELPs is their inverse temperature phase transition behavior. 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.…”

Section: Introductionmentioning

confidence: 99%

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A thermo-responsive protein treatment for dry eyes

Wang

Jashnani

Aluri

et al. 2015

Journal of Controlled Release

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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.

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Section: Methodssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

A thermo-responsive protein treatment for dry eyes

Wang

Jashnani

Aluri

et al. 2015

Journal of Controlled Release

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“…Rapa has been previously demonstrated to bind competitively to an FKBP domain on an FKBP-ELP fusion protein. [19] To further enhance drug-specific encapsulation and improve the drug release, the FKBP domain was genetically fused onto the corona of the nanoparticles formed from SI. This optimized construct FSI was then examined for Rapa encapsulation and release.…”

Section: Introductionmentioning

confidence: 99%

Elastin-based protein polymer nanoparticles carrying drug at both corona and core suppress tumor growth in vivo

Shi

Aluri

Lin

et al. 2013

Journal of Controlled Release

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Numerous nanocarriers of small molecules depend on either non-specific physical encapsulation or direct covalent linkage. In contrast, this manuscript explores an alternative encapsulation strategy based on high-specificity avidity between a small molecule drug and its cognate protein target fused to the corona of protein polymer nanoparticles. With the new strategy, the drug associates tightly to the carrier and releases slowly, which may decrease toxicity and promote tumor accumulation via the enhanced permeability and retention effect. To test this hypothesis, the drug Rapamycin (Rapa) was selected for its potent anti-proliferative properties, which give it immunosuppressant and anti-tumor activity. Despite its potency, Rapa has low solubility, low oral bioavailability, and rapid systemic clearance, which make it an excellent candidate for nanoparticulate drug delivery. To explore this approach, genetically engineered diblock copolymers were constructed from elastin-like polypeptides (ELPs) that assemble small (<100 nm) nanoparticles. ELPs are protein polymers of the sequence (Val-Pro-Gly-Xaa-Gly)n, where the identity of Xaa and n determine their assembly properties. Initially, a screening assay for model drug encapsulation in ELP nanoparticles was developed, which showed that Rose Bengal and Rapa have high non-specific encapsulation in the core of ELP nanoparticles with a sequence where Xaa = Ile or Phe. While excellent at entrapping these drugs, their release was relatively fast (2.2 h half-life) compared to their intended mean residence time in the human body. Having determined that Rapa can be non-specifically entrapped in the core of ELP nanoparticles, FK506 binding protein 12 (FKBP), which is the cognate protein target of Rapa, was genetically fused to the surface of these nanoparticles (FSI) to enhance their avidity towards Rapa. The fusion of FKBP to these nanoparticles slowed the terminal half-life of drug release to 57.8 h. To determine if this class of drug carriers has potential applications in vivo, FSI/Rapa was administered to mice carrying a human breast cancer model (MDA-MB-468). Compared to free drug, FSI encapsulation significantly decreased gross toxicity and enhanced the anti-cancer activity. In conclusion, protein polymer nanoparticles decorated with the cognate receptor of a high potency, low solubility drug (Rapa) efficiently improved drug loading capacity and its release. This approach has applications to the delivery of Rapa and its analogues; furthermore, this strategy has broader applications in the encapsulation, targeting, and release of other potent small molecules.

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“…In the last 2-3 years, multiple articles have been published focusing on these nanocarriers in the delivery of genes and drugs. 6,26,27,29,31,[41][42][43] …”

Section: Polymeric Nanocarriers That Mediate Drug Deliverymentioning

confidence: 99%

“…6 Moreover, FKBP (FK506-binding protein), the cognate receptor of an antiproliferative drug rapamycin (Rapa) has also been genetically fused onto the corona of micelles assembled from the ELP block copolymer ( Figure 3A). 41,42 Because of high-avidity binding of the drug to the receptor, the new fusion protein (FKBP-ELP [FSI]) slowed the terminal half-life of drug release to 57.8 hours ( Figure 3B). 42 The in vivo antitumor and immunosuppressant applications of the new Rapa formulation (FSI-Rapa) were respectively examined in a MDA-MB-468 breast cancer xenograft nude mouse model …”

Section: Elp-mediated Drug Deliverymentioning

confidence: 99%

Genetically engineered nanocarriers for drug delivery

Shi¹,

Gustafson²,

MacKay³

2014

IJN

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Cytotoxicity, low water solubility, rapid clearance from circulation, and off-target side-effects are common drawbacks of conventional small-molecule drugs. To overcome these shortcomings, many multifunctional nanocarriers have been proposed to enhance drug delivery. In concept, multifunctional nanoparticles might carry multiple agents, control release rate, biodegrade, and utilize target-mediated drug delivery; however, the design of these particles presents many challenges at the stage of pharmaceutical development. An emerging solution to improve control over these particles is to turn to genetic engineering. Genetically engineered nanocarriers are precisely controlled in size and structure and can provide specific control over sites for chemical attachment of drugs. Genetically engineered drug carriers that assemble nanostructures including nanoparticles and nanofibers can be polymeric or non-polymeric. This review summarizes the recent development of applications in drug and gene delivery utilizing nanostructures of polymeric genetically engineered drug carriers such as elastin-like polypeptides, silk-like polypeptides, and silk-elastin-like protein polymers, and non-polymeric genetically engineered drug carriers such as vault proteins and viral proteins.

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Switchable Elastin-Like Polypeptides that Respond to Chemical Inducers of Dimerization

Cited by 27 publications

References 40 publications

A thermo-responsive protein treatment for dry eyes

A thermo-responsive protein treatment for dry eyes

Elastin-based protein polymer nanoparticles carrying drug at both corona and core suppress tumor growth in vivo

Genetically engineered nanocarriers for drug delivery

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