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Growth factors, first known for their essential role in the initiation of mitosis, are required for a variety of cellular processes and their localized delivery is considered as a rational approach in their therapeutic application to assure a safe and effective treatment while avoiding unwanted adverse effects. Noncovalent immobilization of growth factors as well as their covalent conjugation is amongst the most common strategies for localized delivery of growth factors. Today, immobilized and covalently conjugated growth factors are considered as a promising drug design and are widely used for protein reformulation and material design to cover the unwanted characteristics of growth factors as well as improving their functions. Selection of a suitable conjugation technique depends on the substrate chemistry and the availability of functional reactive groups in the structure of growth factor, the position of reactive groups in growth factor molecules and its relation with the receptor binding area, and the intention of creating either patterned or unpatterned conjugation. Various approaches for growth factor reformulation have been reported. This review provides an overview on chemical conjugation of growth factors and covers the relevant studies accomplished for bioconjugation of growth factors and their related application.

BackgroundPoly lactic-co-glycolic acid (PLGA) based nanoparticles are considered to be a promising drug carrier in tumor targeting but suffer from the high level of opsonization by reticuloendothelial system due to their hydrophobic structure. As a result surface modification of these nanoparticles has been widely studied as an essential step in their development. Among various surface modifications, human serum albumin (HSA) possesses advantages including small size, hydrophilic surface and accumulation in leaky vasculature of tumors through passive targeting and a probable active transport into tumor tissues.MethodsPLGA nanoparticles of docetaxel were prepared by emulsification evaporation method and were surface conjugated with human serum albumin. Fourier transform infrared spectrum was used to confirm the conjugation reaction where nuclear magnetic resonance was utilized for conjugation ratio determination. In addition, transmission electron microscopy showed two different contrast media in conjugated nanoparticles. Furthermore, cytotoxicity of free docetaxel, unconjugated and conjugated PLGA nanoparticles was studied in HepG2 cells.ResultsSize, zeta potential and drug loading of PLGA nanoparticles were about 199 nm, −11.07 mV, and 4%, respectively where size, zeta potential and drug loading of conjugated nanoparticles were found to be 204 nm, −5.6 mV and 3.6% respectively. Conjugated nanoparticles represented a three-phasic release pattern with a 20% burst effect for docetaxel on the first day. Cytotoxicity experiment showed that the IC50 of HSA conjugated PLGA nanoparticles (5.4 μg) was significantly lower than both free docetaxel (20.2 μg) and unconjugated PLGA nanoparticles (6.2 μg).ConclusionIn conclusion surface modification of PLGA nanoparticles through HSA conjugation results in more cytotoxicity against tumor cell lines compared with free docetaxel and unconjugated PLGA nanoparticles. Albumin conjugated PLGA nanoparticles may represent a promising drug delivery system in cancer therapy.

Oxidative stress associated cell damage is one of the key factors in neurodegeneration development and is highly related to the presence of transition metal ions including iron. Herein, deferasirox, a high affinity iron chelator, was conjugated to lactoferrin molecules by carbodiimide mediated coupling reaction to create a novel drug delivery system with higher brain permeability through receptor mediated transcytosis. Each lactoferrin molecule was averagely attached to 4 to 6 deferasirox molecules resulting in water-soluble conjugated nanostructures which were purified and characterized. Neuroprotective effects of lactoferrin conjugated nanostructures and their cellular uptake were evaluated in differentiated PC12 cell line, and the molecular mechanisms involved in such neuroprotection were elucidated. Lactoferrin conjugates were able to interfere in apoptotic caspase cascade by affecting the expression level of caspase-3, PARP, Bax and Bcl-2. Furthermore, an elevation in the expression level of autophagy markers including Atg7, Atg12-Atg5 and LC3-II/LC3-I ratio was observed. Intraperitoneal injection of lactoferrin conjugates was able to significantly attenuate learning deficits induced by beta amyloid injection in a rat model of Alzheimer's disease, which further confirms a potential neuroprotective effect for lactoferrin conjugated deferasirox in neurodegenerative disorder management through metal chelation therapy.

In this review, Kamalinia et al. discuss mRNA display and its role in peptide and protein design.

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Purpose Most currently-available chemotherapeutic agents target rampant cell division in cancer cells, thereby affecting rapidly-dividing normal cells resulting in toxic side-effects. This non-specificity necessitates identification of novel cellular pathways that are reprogrammed selectively in cancer cells and can be exploited to develop pharmacologically superior and less-toxic therapeutics. Despite growing awareness on dysregulation of lipid metabolism in cancer cells, targeting lipid biosynthesis is still largely uncharted territory. Herein, we report development of a novel non-toxic orally-deliverable anticancer formulation of monoethanolamine (Etn), for prostate cancer by targeting the Kennedy pathway of phosphatidylethanolamine (PE) lipid biosynthesis. Experimental Design We first evaluated GI-tract stability, drug-drug interaction liability, pharmacokinetic and toxicokinetic properties of Etn to evaluate its suitability as a non-toxic orally-deliverable agent. We next performed in vitro and in vivo experiments to investigate efficacy and mechanism of action. Results Our data demonstrate that Etn exhibits excellent bioavailability, GI-tract stability, and no drug-drug interaction liability. Remarkably, orally-fed Etn inhibited tumor growth in four weeks by ~67% in mice bearing human prostate cancer PC-3 xenografts without any apparent toxicity. Mechanistically, Etn exploits selective overexpression of choline kinase in cancer cells, resulting in accumulation of phosphoethanolamine (PhosE), accompanied by downregulation of HIF-1α that induces metabolic stress culminating into cell death. Conclusions Our study provides first evidence for the superior anticancer activity of Etn, a simple lipid precursor formulation, whose non-toxicity conforms to FDA-approved standards, compelling its clinical development for prostate cancer management.

Curcumin, a natural polyphenol, exhibits anti-oxidant, anti-inflammatory, anti-neoplastic and chemopreventive properties. In fact, targeting of this natural anticancer agent has received a great deal of attention during the recent years. In this study, we proposed that curcumin conjugation with lactoferrin molecules may lead to a potential drug delivery system targeted toward cancerous cells through both active and passive targeting. In this regard, curcumin conjugated lactoferrin was developed via a carbodiimide-based coupling reaction and the resulting conjugates were appraised for their molecular properties as a potential targeted drug delivery system. The mean diameter of the designed nanostructure was about 165 ± 26 nm with a PDI of 0.308 ± 0.045. The conjugated nanostructures showed a considerably improved cytotoxicity on HCT116 cells as illustrated by MTT assay along with a higher level of cellular uptake. Cellular uptake and targeting capability of conjugated samples were further investigated by confocal microscopy and the conjugated curcumin nanostructures showed an enhanced efficacy compared to curcumin. Furthermore, flow cytometry analysis proved that early apoptosis occurred in HCT116 cell line, after 24 h incubation with conjugated curcumin.