In-vivo thrombolytic efficacy of RGD modified protein-polymer conjugated urokinase nanogels

AbstractWhile peptide and protein therapeutics have made tremendous advances in clinical treatments over the past few decades, they have been largely hindered by their ability to be effectively delivered to patients. While bolus parenteral injections have become standard clinical practice, they are insufficient to treat diseases that require sustained, local release of therapeutics. Cyclodextrin-based polymers (pCD) have been utilized as a platform to extend the local delivery of small-molecule hydrophobic drugs by leveraging hydrophobic-driven thermodynamic interactions between pCD and payload to extend its release, which has seen success both in vitro and in vivo. Herein, we proposed the novel synthesis of protein-polymer conjugates that are capped with a “high affinity” adamantane. Using bovine serum albumin as a model protein, and anti-interleukin 10 monoclonal antibodies as a functional example, we outline the synthesis of novel protein-polymer conjugates that, when coupled with cyclodextrin delivery platforms, can maintain a sustained release of up to 65 days without largely sacrificing protein structure/function which has significant clinical applications in local antibody-based treatments for immune diseases, cancers, and diabetes.Graphical Abstract

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Modularly engineered injectable hybrid hydrogels based on protein-polymer network as potent immunologic adjuvant in vivo

Biomaterials ◽

10.1016/j.biomaterials.2018.12.034 ◽

2019 ◽

Vol 195 ◽

pp. 100-110 ◽

Cited By ~ 15

Author(s):

V.H. Giang Phan ◽

Huu Thuy Trang Duong ◽

Thavasyappan Thambi ◽

Thanh Loc Nguyen ◽

Md. Hasan Turabee ◽

...

Keyword(s):

Polymer Network ◽

Protein Polymer ◽

Hybrid Hydrogels

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

Journal of Controlled Release ◽

10.1016/j.jconrel.2013.05.013 ◽

2013 ◽

Vol 171 (3) ◽

pp. 330-338 ◽

Cited By ~ 54

Author(s):

Pu Shi ◽

Suhaas Aluri ◽

Yi-An Lin ◽

Mihir Shah ◽

Maria Edman ◽

...

Keyword(s):

Tumor Growth ◽

Polymer Nanoparticles ◽

Protein Polymer

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Trimeric binding of the 70-kD uncoating ATPase to the vertices of clathrin triskelia: a candidate intermediate in the vesicle uncoating reaction.

The Journal of Cell Biology ◽

10.1083/jcb.109.4.1457 ◽

1989 ◽

Vol 109 (4) ◽

pp. 1457-1466 ◽

Cited By ~ 41

Author(s):

J Heuser ◽

C J Steer

Keyword(s):

Atp Hydrolysis ◽

Bovine Brain ◽

Coated Vesicles ◽

Coated Pits ◽

Experimental Conditions ◽

Molecular Conformations ◽

Product Release ◽

Protein Polymer

Clathrin-coated vesicles were uncoated with the 70-kD "uncoating ATPase" from bovine brain, and the molecular products were visualized by freeze-etch electron microscopy. This yielded images of released clathrin triskelia with up to three 70-kD uncoating ATPase molecules bound to their vertices. Likewise, incubation of soluble clathrin triskelia with purified uncoating ATPase also led to trimeric binding of the ATPase to the vertices of clathrin triskelia. However, this occurred only when either EDTA or nonhydrolyzable analogues of ATP were present, in which case the ATPase also appeared to self-associate. When ATP was present instead, no 70-kD ATPases could be found on clathrin triskelia and all ATPases remained monomeric. These observations support the notion that ATP controls an allosteric conversion of the 70-kD uncoating ATPase between two different molecular conformations, an ATP-charged state in which the molecule has relatively low affinity for itself as well as low affinity for clathrin, and an ATP-discharged state in which both of these affinities are high. We presume that in vivo, the latter condition is brought about by ATP hydrolysis and product release, at which point the ATPase will bind tightly to clathrin and/or self-associate. We further propose that these reactions, when occurring in concert within a clathrin lattice, will tend to destabilize it by a mechanism we call "protein polymer competition". We stress the analogies between such a mechanism of uncoating and the ATP-driven events in muscle contraction. Finally, we show that under experimental conditions in which the uncoating ATPase fully removes the coats from brain coated vesicles, identical aliquots of the enzyme do not affect plasmalemmal coated pits in situ. This remarkable selectivity, the mechanism of which remains a complete mystery, is at least consistent with the idea that the 70-kD ATPase indeed plays a role in uncoating coated vesicles after they have formed in vivo.

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Fine Structural Changes in the Microvasculature of the Mouse Pinna: Aging and Radiation Injury

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100050287 ◽

1974 ◽

Vol 32 ◽

pp. 54-55

Author(s):

S. Phyllis Steamer ◽

Rosemarie L. Devine

Keyword(s):

Structural Changes ◽

Radiation Treatment ◽

Arterial Stenosis ◽

Ultrastructural Changes ◽

Vascular Effects ◽

Microvascular Changes ◽

Surrounding Connective Tissue ◽

Fission Neutrons ◽

Total Body

The importance of radiation damage to the skin and its vasculature was recognized by the early radiologists. In more recent studies, vascular effects were shown to involve the endothelium as well as the surrounding connective tissue. Microvascular changes in the mouse pinna were studied in vivo and recorded photographically over a period of 12-18 months. Radiation treatment at 110 days of age was total body exposure to either 240 rad fission neutrons or 855 rad 60Co gamma rays. After in vivo observations in control and irradiated mice, animals were sacrificed for examination of changes in vascular fine structure. Vessels were selected from regions of specific interest that had been identified on photomicrographs. Prominent ultrastructural changes can be attributed to aging as well as to radiation treatment. Of principal concern were determinations of ultrastructural changes associated with venous dilatations, segmental arterial stenosis and tortuosities of both veins and arteries, effects that had been identified on the basis of light microscopic observations. Tortuosities and irregularly dilated vein segments were related to both aging and radiation changes but arterial stenosis was observed only in irradiated animals.

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Induction and Differentiation of Dental Epithelium in Vivo and in Vitro

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053425 ◽

1982 ◽

Vol 40 ◽

pp. 142-145

Author(s):

E. J. Kollar

Keyword(s):

Connective Tissue ◽

Oral Mucosa ◽

Basal Lamina ◽

Functional Derivatives ◽

Specific Source ◽

Dental Epithelium ◽

Connective Tissue Stroma

The differentiation and maintenance of many specialized epithelial structures are dependent on the underlying connective tissue stroma and on an intact basal lamina. These requirements are especially stringent in the development and maintenance of the skin and oral mucosa. The keratinization patterns of thin or thick cornified layers as well as the appearance of specialized functional derivatives such as hair and teeth can be correlated with the specific source of stroma which supports these differentiated expressions.

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Ultrastructural Correlations between Clonal Human Tumor Colonies and in Vivo Neoplasms

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053711 ◽

1982 ◽

Vol 40 ◽

pp. 210-211

Author(s):

M.J. Murphy ◽

R.R. Price ◽

J.C. Sloman

Keyword(s):

Cultured Cells ◽

Human Tumor ◽

Cell Type ◽

Tumor Mass ◽

Initial Cell ◽

Cloning Assay ◽

Human Tumor Cloning ◽

The Relationship

The in vitro human tumor cloning assay originally described by Salmon and Hamburger has been applied recently to the investigation of differential anti-tumor drug sensitivities over a broad range of human neoplasms. A major problem in the acceptance of this technique has been the question of the relationship between the cultured cells and the original patient tumor, i.e., whether the colonies that develop derive from the neoplasm or from some other cell type within the initial cell population. A study of the ultrastructural morphology of the cultured cells vs. patient tumor has therefore been undertaken to resolve this question. Direct correlation was assured by division of a common tumor mass at surgical resection, one biopsy being fixed for TEM studies, the second being rapidly transported to the laboratory for culture.

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Structural analysis of the photosynthetic membrane from Ectothiorhodospira halochloris

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010007727x ◽

1983 ◽

Vol 41 ◽

pp. 740-741

Author(s):

H. Engelhardt ◽

R. Guckenberger ◽

W. Baumeister

Keyword(s):

Lattice Structure ◽

Bacterial Species ◽

Hexagonal Lattice ◽

Reaction Centre ◽

Photosynthetic Membrane ◽

Rhodopseudomonas Viridis ◽

Photosynthetic Membranes ◽

Ectothiorhodospira Halochloris ◽

Main Components

Bacterial photosynthetic membranes contain, apart from lipids and electron transport components, reaction centre (RC) and light harvesting (LH) polypeptides as the main components. The RC-LH complexes in Rhodopseudomonas viridis membranes are known since quite seme time to form a hexagonal lattice structure in vivo; hence this membrane attracted the particular attention of electron microscopists. Contrary to previous claims in the literature we found, however, that 2-D periodically organized photosynthetic membranes are not a unique feature of Rhodopseudomonas viridis. At least five bacterial species, all bacteriophyll b - containing, possess membranes with the RC-LH complexes regularly arrayed. All these membranes appear to have a similar lattice structure and fine-morphology. The lattice spacings of the Ectothiorhodospira haloohloris, Ectothiorhodospira abdelmalekii and Rhodopseudomonas viridis membranes are close to 13 nm, those of Thiocapsa pfennigii and Rhodopseudomonas sulfoviridis are slightly smaller (∼12.5 nm).

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