Recombinant protein-based polymers for advanced drug delivery.

Advances in recombinant techniques have led to the development of genetically engineered polymers with exquisite control over monomer sequence and polymer length. The ability to study how precise structures correlate with function has provided opportunities for the utility of these polymers in drug delivery. Chemically derived and developed methods of synthesis have yielded many useful polymers for drug delivery to-date, including those currently used in patients. However they have drawbacks, including limitations involved in statistical characterization of conventional polymer synthetic techniques. Encoding at the genetic level and production of such recombinant polymers in organisms allow for precise order and accuracy of amino acid residues and production of monodisperse polymers with specific function and physicochemical properties. Research into elastin-like, silk-like, and silk-elastinlike protein polymers for example has led to the development of delivery systems based on natural motifs of structural proteins to take advantage of their physicochemical properties. Additionally, protein based polymers on other natural motifs and de novo designs are starting to produce promising constructs for drug and gene delivery applications where precise control over structure promises correlation with function and guides the development of new and improved constructs. Clinical applications based on recombinant polymers for delivery of bioactive agents have not been realized at this point. However lessons learned from fundamental research with these polymers can be used to guide design of safe and effective systems for use in the clinic. This tutorial review summarizes progress made in the design and utility of recombinant polymers in drug and gene delivery and discusses challenges and future directions of such polymers for this purpose.

[1]  Elliot L Chaikof,et al.  Elastin-mimetic protein polymers capable of physical and chemical crosslinking. , 2009, Biomaterials.

[2]  Jonathan R. McDaniel,et al.  Fabrication of elastin-like polypeptide nanoparticles for drug delivery by electrospraying. , 2009, Biomacromolecules.

[3]  J. Cappello,et al.  The biological production of protein polymers and their use. , 1990, Trends in biotechnology.

[4]  D. Wirtz,et al.  Reversible hydrogels from self-assembling artificial proteins. , 1998, Science.

[5]  V. Conticello,et al.  Investigation of the dynamics of an elastin‐mimetic polypeptide using solid‐state NMR , 2004, Magnetic resonance in chemistry : MRC.

[6]  Ashutosh Chilkoti,et al.  Self-assembling chimeric polypeptide-doxorubicin conjugate nanoparticles that abolish tumors after a single injection , 2009, Nature materials.

[7]  José Carlos Rodríguez-Cabello,et al.  Thermal Behavior and Kinetic Analysis of the Chain Unfolding and Refolding and of the Concomitant Nonpolar Solvation and Desolvation of Two Elastin-like Polymers , 2003 .

[8]  K. Kiick,et al.  Multivalent protein polymers with controlled chemical and physical properties. , 2010, Advanced drug delivery reviews.

[9]  H. Ghandehari,et al.  Thermal analysis of water in silk-elastinlike hydrogels by differential scanning calorimetry. , 2004, Biomacromolecules.

[10]  C. Venkatachalam,et al.  Conformation characterization of cyclopentapeptide, L.Val-L.Pro-Gly-L.Val-Gly: a repeating analogue of elastin. , 2009, International journal of peptide and protein research.

[11]  J. Cappello Protein engineering for biomaterials applications , 1992 .

[12]  Larisa C Wu,et al.  Hybrid hydrogels self-assembled from graft copolymers containing complementary β-sheets as hydroxyapatite nucleation scaffolds. , 2011, Biomaterials.

[13]  K. Lees,et al.  The therapeutic time window--theoretical and practical considerations. , 2000, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[14]  K. Kiick,et al.  Evaluation of Conformation and Association Behavior of Multivalent Alanine-Rich Polypeptides , 2008, Pharmaceutical Research.

[15]  Keiji Numata,et al.  Gene delivery mediated by recombinant silk proteins containing cationic and cell binding motifs. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[16]  Y. Bae,et al.  Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[17]  Stefan Rose-John,et al.  Elastin-like polypeptides revolutionize recombinant protein expression and their biomedical application. , 2010, Trends in biotechnology.

[18]  Hamidreza Ghandehari,et al.  Silk-elastin-like hydrogel improves the safety of adenovirus-mediated gene-directed enzyme-prodrug therapy. , 2010, Molecular pharmaceutics.

[19]  Hamidreza Ghandehari,et al.  Genetic synthesis and characterization of pH- and temperature-sensitive silk-elastinlike protein block copolymers. , 2002, Journal of biomedical materials research.

[20]  Yuhua Wang,et al.  HSV-TK/GCV cancer suicide gene therapy by a designed recombinant multifunctional vector. , 2011, Nanomedicine : nanotechnology, biology, and medicine.

[21]  David L Kaplan,et al.  Genetic engineering of fibrous proteins: spider dragline silk and collagen. , 2002, Advanced drug delivery reviews.

[22]  A. Chilkoti,et al.  Structural optimization of a "smart" doxorubicin-polypeptide conjugate for thermally targeted delivery to solid tumors. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[23]  M. Dewhirst,et al.  Targeting a genetically engineered elastin-like polypeptide to solid tumors by local hyperthermia. , 2001, Cancer research.

[24]  C. Venkatachalam,et al.  Nuclear Overhauser effect and computational characterization of the beta-spiral of the polypentapeptide of elastin. , 1989, Journal of biomolecular structure & dynamics.

[25]  Hamidreza Ghandehari,et al.  Silk-elastinlike protein polymer hydrogels for localized adenoviral gene therapy of head and neck tumors. , 2009, Biomacromolecules.

[26]  D. Kaplan,et al.  Silk-based delivery systems of bioactive molecules. , 2010, Advanced drug delivery reviews.

[27]  Hamidreza Ghandehari,et al.  Influence of polymer structure and biodegradation on DNA release from silk-elastinlike protein polymer hydrogels. , 2009, International journal of pharmaceutics.

[28]  C. R. Middaugh,et al.  Characterization of the Changes in Secondary Structure and Architecture of Elastin−Mimetic Triblock Polypeptides during Thermal Gelation , 2006 .

[29]  Dan W. Urry,et al.  What Sustains Life?: Consilient Mechanisms for Protein-Based Machines and Materials , 2006 .

[30]  Allan S. Hoffman,et al.  The origins and evolution of "controlled" drug delivery systems. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[31]  Jeffrey M. Caves,et al.  Deformation responses of a physically cross-linked high molecular weight elastin-like protein polymer. , 2008, Biomacromolecules.

[32]  D. Urry,et al.  Chemical potential driven contraction and relaxation by ionic strength modulation of an inverse temperature transition , 1988 .

[33]  J. Magda,et al.  Fabrication of highly uniform nanoparticles from recombinant silk-elastin-like protein polymers for therapeutic agent delivery. , 2011, ACS nano.

[34]  W R Gray,et al.  Isolation and amino acid sequences of tropoelastin peptides. , 1973, The Journal of biological chemistry.

[35]  M. Haider,et al.  Molecular engineering of silk-elastinlike polymers for matrix-mediated gene delivery: biosynthesis and characterization. , 2005, Molecular pharmaceutics.

[36]  G. Bidwell,et al.  Evaluation of cell penetrating peptides fused to elastin-like polypeptide for drug delivery. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[37]  Hamidreza Ghandehari,et al.  Solute diffusion in genetically engineered silk-elastinlike protein polymer hydrogels. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[38]  M. Marquet,et al.  Genetic Engineering of Structural Protein Polymers , 1990, Biotechnology progress.

[39]  Chikako Tanaka,et al.  Synthesis and characterization of cell-adhesive silk-like proteins constructed from the sequences of Anaphe silk fibroin and fibronectin. , 2009, Biomacromolecules.

[40]  A. Chilkoti,et al.  Tumor accumulation, degradation and pharmacokinetics of elastin-like polypeptides in nude mice. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[41]  F. Ungaro,et al.  Microsphere-integrated drug-eluting stents: PLGA microsphere integration in hydrogel coating for local and prolonged delivery of hydrophilic antirestenosis agents. , 2011, Journal of biomedical materials research. Part A.

[42]  M. Francis,et al.  Using synthetically modified proteins to make new materials. , 2011, Accounts of chemical research.

[43]  Kazunori Kataoka,et al.  Current state, achievements, and future prospects of polymeric micelles as nanocarriers for drug and gene delivery. , 2006, Pharmacology & therapeutics.

[44]  J. Kopeček,et al.  Coiled-coil based drug-free macromolecular therapeutics: in vivo efficacy. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[45]  E. Chaikof,et al.  Recombinant elastin-mimetic biomaterials: Emerging applications in medicine. , 2010, Advanced drug delivery reviews.

[46]  H. Maeda,et al.  Exploiting the enhanced permeability and retention effect for tumor targeting. , 2006, Drug discovery today.

[47]  Ashutosh Chilkoti,et al.  Quantification of the effects of chain length and concentration on the thermal behavior of elastin-like polypeptides. , 2004, Biomacromolecules.

[48]  M. Haider,et al.  Genetically engineered polymers: status and prospects for controlled release. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[49]  Zhenghua Zhu,et al.  Improving cell-adhesive properties of recombinant Bombyx mori silk by incorporation of collagen or fibronectin derived peptides produced by transgenic silkworms. , 2007, Biomacromolecules.

[50]  D. Kirschner,et al.  Designing recombinant spider silk proteins to control assembly. , 1999, International journal of biological macromolecules.

[51]  S. Hoag,et al.  Influence of solute charge and hydrophobicity on partitioning and diffusion in a genetically engineered silk-elastin-like protein polymer hydrogel. , 2010, Macromolecular bioscience.

[52]  Hamidreza Ghandehari,et al.  Silk-elastinlike protein polymers for matrix-mediated cancer gene therapy. , 2010, Advanced drug delivery reviews.

[53]  Yuhua Wang,et al.  Development of targeted recombinant polymers that can deliver siRNA to the cytoplasm and plasmid DNA to the cell nucleus. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[54]  J. Cappello,et al.  In-situ self-assembling protein polymer gel systems for administration, delivery, and release of drugs. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[55]  G. Bidwell,et al.  Cell penetrating elastin-like polypeptides for therapeutic peptide delivery. , 2010, Advanced drug delivery reviews.

[56]  M. Nowicki,et al.  Elastic-contractile model proteins: Physical chemistry, protein function and drug design and delivery. , 2010, Advanced drug delivery reviews.

[57]  Liang Feng,et al.  Simple bioseparations using self-cleaving elastin-like polypeptide tags , 2005, Nature Methods.

[58]  L. Meinel,et al.  Silk fibroin as a vehicle for drug delivery applications. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[59]  Keiji Numata,et al.  Bioengineered silk protein-based gene delivery systems. , 2009, Biomaterials.

[60]  Joseph Cappello,et al.  Genetic Production of Synthetic Protein Polymers , 1992 .

[61]  James A Van Deventer,et al.  Residue-specific incorporation of non-canonical amino acids into proteins: recent developments and applications. , 2010, Current opinion in chemical biology.

[62]  T. M. Parker,et al.  Section: Extracellular matrix proteins; Mechanics of elastin: molecular mechanism of biological elasticity and its relationship to contraction , 2002, Journal of Muscle Research & Cell Motility.

[63]  Jonathan R. McDaniel,et al.  Injectable intratumoral depot of thermally responsive polypeptide-radionuclide conjugates delays tumor progression in a mouse model. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[64]  Yuhua Wang,et al.  Biosynthesis and characterization of a novel genetically engineered polymer for targeted gene transfer to cancer cells. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[65]  Hamidreza Ghandehari,et al.  Characterization and real-time imaging of gene expression of adenovirus embedded silk-elastinlike protein polymer hydrogels. , 2008, Molecular pharmaceutics.

[66]  Keiji Numata,et al.  Silk-based gene carriers with cell membrane destabilizing peptides. , 2010, Biomacromolecules.

[67]  Hamidreza Ghandehari,et al.  Comparison of silk-elastinlike protein polymer hydrogel and poloxamer in matrix-mediated gene delivery. , 2012, International journal of pharmaceutics.

[68]  Hamidreza Ghandehari,et al.  Silk‐elastinlike protein polymers improve the efficacy of adenovirus thymidine kinase enzyme prodrug therapy of head and neck tumors , 2010, The journal of gene medicine.

[69]  Ashutosh Chilkoti,et al.  Genetically encoded synthesis of protein-based polymers with precisely specified molecular weight and sequence by recursive directional ligation: examples from the elastin-like polypeptide system. , 2002, Biomacromolecules.

[70]  N Vaidehi,et al.  Stabilization of coiled-coil peptide domains by introduction of trifluoroleucine. , 2001, Biochemistry.

[71]  C. Morrow,et al.  Production and Purification of a Recombinant Elastomeric Polypeptide, G‐(VPGVG)19‐VPGV, from Escherichia coli , 1992, Biotechnology progress.

[72]  D. Tirrell,et al.  Engineering the extracellular matrix: a novel approach to polymeric biomaterials. I. Control of the physical properties of artificial protein matrices designed to support adhesion of vascular endothelial cells. , 2000, Biomacromolecules.

[73]  M. Dewhirst,et al.  Drug targeting using thermally responsive polymers and local hyperthermia. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[74]  Hamidreza Ghandehari,et al.  Silk-elastinlike recombinant polymers for gene therapy of head and neck cancer: from molecular definition to controlled gene expression. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[75]  A. Hatefi,et al.  Development of recombinant cationic polymers for gene therapy research. , 2010, Advanced drug delivery reviews.

[76]  Ashutosh Chilkoti,et al.  Evaluation of an elastin-like polypeptide-doxorubicin conjugate for cancer therapy. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[77]  T. M. Parker,et al.  Mechanics of elastin: molecular mechanism of biological elasticity and its relationship to contraction , 2003 .

[78]  F. Yuan,et al.  A novel method for viral gene delivery in solid tumors. , 2005, Cancer research.

[79]  D. Martin,et al.  Morphology and primary crystal structure of a silk‐like protein polymer synthesized by genetically engineered Escherichia coli bacteria , 1994, Biopolymers.

[80]  T. M. Parker,et al.  Elastin: a representative ideal protein elastomer. , 2002, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[81]  A. Hatefi,et al.  Recombinant polymer‐protein fusion: a promising approach towards efficient and targeted gene delivery , 2006, The journal of gene medicine.

[82]  D. Urry,et al.  Phase‐structure transitions of the elastin polypentapeptide–water system within the framework of composition–temperature studies , 1985, Biopolymers.

[83]  E. Chaikof,et al.  Micelle density regulated by a reversible switch of protein secondary structure. , 2006, Journal of the American Chemical Society.

[84]  E. Chaikof,et al.  The effect of a recombinant elastin-mimetic coating of an ePTFE prosthesis on acute thrombogenicity in a baboon arteriovenous shunt. , 2007, Biomaterials.

[85]  D. Urry,et al.  Polypentapeptide of elastin: temperature dependence correlation of elastomeric force and dielectric permittivity. , 1984, Biochemical and biophysical research communications.

[86]  Doris Kaufmann,et al.  Efficient synthesis of protein-drug conjugates using a functionalizable recombinant elastin-mimetic polypeptide. , 2006, Macromolecular bioscience.

[87]  A. Cresce,et al.  Silk–elastinlike protein polymer hydrogels: Influence of monomer sequence on physicochemical properties , 2009 .

[88]  Ick Chan Kwon,et al.  Engineered polymers for advanced drug delivery. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.