Synthesis of Protein Nano-Conjugates for Cancer Therapy
Protein−polymer conjugates synthesized by this novel technique ..
Synthesis of Uniform Protein−Polymer ..
In addition to organic coatings, core-shell structures, such as biocompatible silica- or gold-covered magnetic nanoparticles, have provided an attractive approach to developing stealth nanoparticles. Silica shells serve as protective stable nanoparticle coatings under aqueous conditions. The ability to encapsulate functional molecules within the nanoparticle matrix is a unique feature of these nanostructures. Hyeon and Moon developed Fe3O4 nanocrystal-embedded, core-shell mesoporous silica nanoparticles, and they demonstrated their multifunctional application to simultaneous MR/optical imaging and drug delivery . This study suggested a precise method for controlling the size of the silica nanoparticles smaller than 100 nm. The surfactant cetyltrimethylammonium bromide (CTAB) provided an organic template for the formation of a mesoporous silica shell and stabilized the hydrophobic Fe3O4 nanocrystals in an aqueous solution. The sol-gel process occurred through the template by using tetraethylorthosilicate (TEOS) and rhodamine B isothiocyanate (RITC)-labeled aminopropyltriethoxysilane (APS), and generated amine groups containing silica shell, to which PEG was covalently conjugated via succinimidyl end group to render further biocompatibility. Dox molecules loaded onto the as-synthesized Fe3O4@mSiO2(R)-PEG NPs to convey therapeutic properties. The core-shell structure exhibited magnetic and fluorescent properties, as well as a therapeutic index, suggesting the utility of the nanostructure in biomedical theranostic applications. On the other hand, gold provides several advantages as a coating material due to its inertness and its unique ability to absorb near-IR radiation. Hyeon and Cho described magnetic gold nanoshells (Mag-GNS) consisting of gold nanoshells encapsulating magnetic Fe3O4 nanoparticles as a novel nanomedical platform for simultaneous diagnostic imaging and thermal therapy . Monodisperse 7 nm Fe3O4 nanoparticles stabilized with 2-bromo-2-methylpropionic acid (BMPA) were covalently attached to amino-modified silica spheres through a direct nucleophilic substitution reaction between the bromo groups and the amino groups. Gold seed nanoparticles were then attached to the residual amino groups of the silica spheres. Finally, a complete 15 nm thick gold shell embedded with Fe3O4 nanoparticles formed around the silica spheres to generate Mag-GNS. To target breast cancer, an anti-HER2/neu antibody was conjugated onto the surfaces of the Mag-GNS. SKBR3 breast cancer cells treated with Mag-GNS could be detected using a clinical MRI system, followed by selective destruction by near-IR radiation.
N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-RGD (Arg-Gly-Asp) conjugates targeting the αvβ3 integrin present on angiogenic blood vessels and some tumor types have shown increased accumulation in solid tumors and possess properties that suggest their use for site-specific drug delivery. Geldanamycin (GDM) is a benzoquinoid ansamycin that binds to heat-shock protein 90 (HSP90), effective for the treatment of multiple cancer types including prostate, but has dose-limiting cytotoxicity. We recently reported the synthesis of HPMA copolymer-aminohexyl-geldanamycin (AH-GDM) conjugates containing RGDfK that demonstrated favorable properties of drug release, in vitro binding to the αvβ3 integrin, cytotoxicity in human prostate cancer cells, and tolerability in nude mice greater than 2-fold equivalent free drug doses. In this study the biodistribution of 125I-radiolabeled HPMA copolymer-AH-GDM conjugates with and without RGDfK in both non-tumor and DU145 prostate tumor xenograft-bearing nude mice was evaluated. At 60 mg/kg drug equivalent polymer doses in non-tumor bearing mice both conjugates showed fast elimination from blood and decreasing accumulation in all other organs. Kidney accumulation predominated and was higher for the conjugate containing RGDfK. In tumor bearing mice, trace quantities of the conjugate containing RGDfK showed increased tumor accumulation as compared to the conjugate without RGDfK. Also evaluated were free drug concentrations in prostate tumor xenografts following treatments of 30 and 60 mg/kg drug-equivalent copolymer-conjugates (with and without RGDfK) compared with 30 mg/kg free AH-GDM. Overall, 60 mg/kg treatment of RGDfK-containing conjugate showed significantly higher (p
Example of protein synthesis inhibitor
Superparamagnetic iron oxide (SPIO) nanoparticles have become a popular strategy of cancer treatment and molecular imaging because of their versatile properties and biocompatibility. A variety of studies have shown the exciting potential of functionalized SPIO nanoparticles, such as surface-coated, targeted ligand-conjugated, and/or drug-loaded SPIO nanoparticles, as powerful tools for targeted imaging and therapy. Moreover, the applications of SPIO nanoparticles that integrate diagnosis and therapy in SPIO nanoparticles facilitate the monitoring of therapeutic efficacy during treatment. In the present review, we primarily concentrate on the recent advancements in the field of SPIO nanoparticles in terms of synthesis, targeted therapy, and cancer imaging.
Lee decorated liposomal Dox with a lung tumor targeted peptide . Lung cancer is the leading cause of death due to cancer, and its high mortality rate appears to derive from a low therapeutic index for chemotherapy and late detection due to a lack of sensitive diagnostic biomarkers . The identification of novel biomarkers for early lung cancer detection remains a challenge. In this study, a novel peptide (CSNIDARAC) with a high binding affinity for lung tumors was identified by screening of a phage display peptide library, and CSNIDARAC peptide-conjugated liposomal Dox (Lipo-Dox) was synthesized. The tumor targeting capabilities and the therapeutic efficacy were evaluated in the H460 tumor xenograft mice. To minimize the interactions between the targeted peptide and the surface of the liposome, the amount of PEG on the surface of the liposome was reduced from 5-20 mol% (general use) to 1.3 mol% of total lipids. Tumor growth inhibition of the peptide-targeted Lipo-Dox was superior to that of the untargeted Lipo-Dox or free Dox administered at an equivalent dose, and this result was consistent with the levels of apoptosis measured by TUNEL staining. Near-IR Cy7.5 dye-labeled peptide-conjugated Lipo-Dox also showed a distinct fluorescence signal at the tumor, whereas untargeted Lipo-Dox did not show such a strong signal intensity, suggesting the potential utility of this lung tumor-targeting peptide as a diagnostic agent.
As conjugation often affects the protein structure and function, ..
Potential biomedical applications of nanoparticles also depend greatly on their biocompatibility. Therefore, the cytotoxicity of Ag-protein bio-conjugates was examined under in vitro conditions in the mouse fibroblast cell line 3T3. This was assessed in terms of the effect of Ag-protein bio-conjugates on cell viability, determined by CCK-8 assay. After treatment with Ag-protein bio-conjugates for 24 hours, it was demonstrated that viability remains above 80% when the Ag-protein bio-conjugate concentration remained below 12 μg/mL (). It has been reported that some Ag nanoparticles produce significant toxicity in cell culture media, while protein-coated Ag nanoparticles show minimal or no toxicity in a 3T3 cell culture, which is consistent with the results of cinnamon phytochemical-coated Au nanoparticles. A possible explanation is that both of these are naturally occurring biomolecules that have evolved and have been proven safe in the human body., They supply a nontoxic coating for Ag nanoparticles, which provides biocompatibility for in vivo administrations. The lack of any noticeable toxicity of Ag-protein bio-conjugates thus presents new opportunities for safe delivery and applications of such nanopharmacuticals in molecular therapy.
The folate receptor (FR) is a potentially useful biological target for the management of many human cancers. This membrane protein binds extracellular folates with very high affinity and, through an endocytic process, physically delivers them inside the cell for biological consumption. There are now many examples of how this physiological system can be exploited for the targeted delivery of biologically active molecules to cancer. In fact, strong preclinical as well as emerging clinical evidence exists showing how FR-positive cancers can be (i) anatomically identified using folate conjugates of radiodiagnostic imaging agents and (ii) effectively treated with companion folate-targeted chemotherapies. While the biological results are compelling, it is of equal importance to understand the conjugation chemistries that were developed to produce these active molecules. Therefore, this review will focus on the methods utilized to construct folate-based small-molecule drug conjugates (SMDCs), with particular attention focused on modular design, hydrophilic spacers, and self-immolative linkers.
Polyisoprenoyl gemcitabine conjugates self assemble …
, useful for cancer therapy Andrei ..
Antibody–drug conjugates ..
Colloidal Gold-Antibody and Protein Conjugates
4526714 Conjugates of anticoagulant and protein
Antibody drug conjugates ..
Multifunctional Aptamer-miRNA Conjugates for Targeted Cancer Therapy.
In recent years, multifunctional nanoparticles (NPs) consisting of either metal (e.g. Au), or magnetic NP (e.g. iron oxide) with other fluorescent components such as quantum dots (QDs) or organic dyes have been emerging as versatile candidate systems for cancer diagnosis, therapy, and macromolecule delivery such as micro ribonucleic acid (microRNA). This review intends to highlight the recent advances in the synthesis and application of multifunctional NPs (mainly iron oxide) in theranostics, an area used to combine therapeutics and diagnostics. The recent applications of NPs in miRNA delivery are also reviewed.
Engineering Folate–Drug Conjugates to Target Cancer: …
The research on superparamagnetic iron oxide nanoparticles (SPIONs) has been growing exponentially over the last several years. The field continues to drive in the direction of biomedical applications, especially molecular therapeutics by exploiting the immense qualities of SPIONs . This includes the distinctive controllable properties such as size, shape, magnetism, crystallinity and flexibility in fabricating multifunctional SPIONs with fluorescence, targeting ligands, drugs etc, thanks to the advancements in the syntheses and functionalization techniques developed hitherto. There are some excellent synthetic methods in prior arts on the formation of superparamagnetic magnetite (Fe3O4) and maghemite (γ-Fe2O3) SPIONs, with size control, narrow distribution, water solubility and surface functionalization [-]. The co-precipitation method is a conventional synthetic paradigm where Fe(II) and Fe(III) salts are co-precipitated in a basic solution in the presence of coating materials such as polymer or dextran (or its derivatives). Although the resulted iron oxide nanoparticles (NPs) are larger in size (ca. 100 nm) and partially crystalline, the particles are readily water soluble where their surfaces are directly functionalized. Alternatively, thermal decomposition method using precursors such as Fe(CO)5, Fe(Stearate)2, with high boiling solvents (octadecene, benzyl ether) and surfactants/ligands (oleic acid, oleylamine) can be used to synthesize smaller sized hydrophobic SPIONs (5-10 nm). In order to impart the SPIONs with water solubility for biomedical applications, water-oil microemulsion method can be employed as a reaction medium for coating a hydrophilic ligand (e.g. silica, peptides) on the hydrophobic surface.
Antibody Drug Conjugates - A new way to treat cancer
In this project funded by the Macromolecular, Supramolecular and Nanochemistry Program of the Chemistry Division, Jon Pokorski and Nicole Steinmetz of Case Western Reserve University will develop methods to form complex polymeric nanostructures based on the templated polymer growth from a biological scaffold, specifically tobacco mosaic virus (TMV). The bottom-up synthesis of polymeric nanoparticles with controlled sizes and features, such as ligand spacing is a critical need in nanoscience. The approach involves exploring three methods to synthesize rod-shaped nanostructures: 1) using ATRP to graft polymers from the exterior of TMV, 2) grafting polymers from the interior surface of TMV, followed by removal of the template to yield high-aspect ratio polymeric nanoparticles, and 3) polymerize both on the interior and exterior surface to yield complex inside-out polymeric nanoparticles. The template surface can be modified using genetic engineering methods in order to increase or decrease the particle dimensions in a rational manner. Organizing functional molecules in deterministic arrays provides a means to chemically program new functional devices for applications in medicine and energy. The broader impacts of the project also involve training graduate and undergraduate students, as well as participation in the Polymer Envoy Program for training high school students in Cleveland's school districts.
The creation of precisely defined structures that have dimensions on the order of nanometers (termed "nanostructures") continues to be a challenge for chemists. Nature has perfected the assembly of proteins into a myriad of nanostructures, particularly in the case of viruses. This project will develop new and innovative ways to synthesize these materials in a highly pure form using viruses as a scaffold for further materials synthesis. These types of virus-templated nanomaterials could find applications as promising platforms for drug delivery or as connecting elements in nanoelectronics.
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