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Elastin-based protein polymer nanoparticles carrying drug at both corona and core suppress tumor growth in vivo.
J Control Release. 2013 Nov 10; 171(3):330-8.JC

Abstract

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 (<100nm) 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 (2.2h 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 57.8h. 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 analogs; furthermore, this strategy has broader applications in the encapsulation, targeting, and release of other potent small molecules.

Authors+Show Affiliations

Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, 90089, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23714121

Citation

Shi, Pu, et al. "Elastin-based Protein Polymer Nanoparticles Carrying Drug at Both Corona and Core Suppress Tumor Growth in Vivo." Journal of Controlled Release : Official Journal of the Controlled Release Society, vol. 171, no. 3, 2013, pp. 330-8.
Shi P, Aluri S, Lin YA, et al. Elastin-based protein polymer nanoparticles carrying drug at both corona and core suppress tumor growth in vivo. J Control Release. 2013;171(3):330-8.
Shi, P., Aluri, S., Lin, Y. A., Shah, M., Edman, M., Dhandhukia, J., Cui, H., & MacKay, J. A. (2013). Elastin-based protein polymer nanoparticles carrying drug at both corona and core suppress tumor growth in vivo. Journal of Controlled Release : Official Journal of the Controlled Release Society, 171(3), 330-8. https://doi.org/10.1016/j.jconrel.2013.05.013
Shi P, et al. Elastin-based Protein Polymer Nanoparticles Carrying Drug at Both Corona and Core Suppress Tumor Growth in Vivo. J Control Release. 2013 Nov 10;171(3):330-8. PubMed PMID: 23714121.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Elastin-based protein polymer nanoparticles carrying drug at both corona and core suppress tumor growth in vivo. AU - Shi,Pu, AU - Aluri,Suhaas, AU - Lin,Yi-An, AU - Shah,Mihir, AU - Edman,Maria, AU - Dhandhukia,Jugal, AU - Cui,Honggang, AU - MacKay,J Andrew, Y1 - 2013/05/25/ PY - 2013/03/14/received PY - 2013/05/09/revised PY - 2013/05/18/accepted PY - 2013/5/30/entrez PY - 2013/5/30/pubmed PY - 2014/5/6/medline KW - CMC KW - CMT KW - DLS KW - ELPs KW - Elastin-like polypeptide KW - FK506 binding protein 12 KW - FKBP KW - High-specificity avidity KW - ITC KW - Nanoparticulate drug delivery KW - Protein polymer KW - Rapa KW - Rapamycin encapsulation KW - TEM KW - critical micelle concentration KW - critical micelle temperature KW - cryo-TEM KW - cryogenic-transmission electron microscopy KW - dynamic light scattering KW - elastin-like polypeptides KW - inverse transition cycling KW - mTOR KW - mammalian target of rapamycin KW - rapamycin KW - transmission electron microscopy SP - 330 EP - 8 JF - Journal of controlled release : official journal of the Controlled Release Society JO - J Control Release VL - 171 IS - 3 N2 - 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 (<100nm) 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 (2.2h 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 57.8h. 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 analogs; furthermore, this strategy has broader applications in the encapsulation, targeting, and release of other potent small molecules. SN - 1873-4995 UR - https://www.unboundmedicine.com/medline/citation/23714121/Elastin_based_protein_polymer_nanoparticles_carrying_drug_at_both_corona_and_core_suppress_tumor_growth_in_vivo_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-3659(13)00285-X DB - PRIME DP - Unbound Medicine ER -