Inorganic/organic combination: Inorganic particles/polymer composites for tissue engineering applications.

Biomaterials have ushered the field of tissue engineering and regeneration into a new era with the development of advanced composites. Among these, the composites of inorganic materials with organic polymers present unique structural and biochemical properties equivalent to naturally occurring hybrid systems such as bones, and thus are highly desired. The last decade has witnessed a steady increase in research on such systems with the focus being on mimicking the peculiar properties of inorganic/organic combination composites in nature. In this review, we discuss the recent progress on the use of inorganic particle/polymer composites for tissue engineering and regenerative medicine. We have elaborated the advantages of inorganic particle/polymer composites over their organic particle-based composite counterparts. As the inorganic particles play a crucial role in defining the features and regenerative capacity of such composites, the review puts a special emphasis on the various types of inorganic particles used in inorganic particle/polymer composites. The inorganic particles that are covered in this review are categorised into two broad types (1) solid (e.g., calcium phosphate, hydroxyapatite, etc.) and (2) porous particles (e.g., mesoporous silica, porous silicon etc.), which are elaborated in detail with recent examples. The review also covers other new types of inorganic material (e.g., 2D inorganic materials, clays, etc.) based polymer composites for tissue engineering applications. Lastly, we provide our expert analysis and opinion of the field focusing on the limitations of the currently used inorganic/organic combination composites and the immense potential of new generation of composites that are in development.

Cerium Oxide Nanoparticles with Entrapped Gadolinium for High T 1 Relaxivity and ROS-Scavenging Purposes.

Gadolinium chelates are employed worldwide today as clinical contrast agents for magnetic resonance imaging. Until now, the commonly used linear contrast agents based on the rare-earth element gadolinium have been considered safe and well-tolerated. Recently, concerns regarding this type of contrast agent have been reported, which is why there is an urgent need to develop the next generation of stable contrast agents with enhanced spin-lattice relaxation, as measured by improved T 1 relaxivity at lower doses. Here, we show that by the integration of gadolinium ions in cerium oxide nanoparticles, a stable crystalline 5 nm sized nanoparticulate system with a homogeneous gadolinium ion distribution is obtained. These cerium oxide nanoparticles with entrapped gadolinium deliver strong T 1 relaxivity per gadolinium ion (T 1 relaxivity, r 1 = 12.0 mM-1 s-1) with the potential to act as scavengers of reactive oxygen species (ROS). The presence of Ce3+ sites and oxygen vacancies at the surface plays a critical role in providing the antioxidant properties. The characterization of radial distribution of Ce3+ and Ce4+ oxidation states indicated a higher concentration of Ce3+ at the nanoparticle surfaces. Additionally, we investigated the ROS-scavenging capabilities of pure gadolinium-containing cerium oxide nanoparticles by bioluminescent imaging in vivo, where inhibitory effects on ROS activity are shown.

Microencapsulated islet-like microtissues with toroid geometry for enhanced cellular viability.

Transplantation of immuno-isolated islets is a promising strategy to restore insulin-secreting function in patients with Type 1 diabetes. However, the clinical translation of this treatment approach remains elusive due to the loss of islet viability resulting from hypoxia at the avascular transplantation site. To address this challenge, we designed non-spherical islet-like microtissues and investigated the effect of their geometries on cellular viability. Insulin-secreting microtissues with different shapes were fabricated by assembly of monodispersed rat insulinoma beta cells on micromolded nonadhesive hydrogels. Our study quantitatively demonstrated that toroid microtissues exhibited enhanced cellular viability and metabolic activity compared to rod and spheroid microtissues with the same volume. At a similar level of cellular viability, toroid geometry facilitated efficient packing of more cells into each microtissue than rod and spheroid geometries. In addition, toroid microtissues maintained the characteristic glucose-responsive insulin secretion of rat insulinoma beta cells. Furthermore, toroid microtissues preserved their geometry and structural integrity following their microencapsulation in immuno-isolatory alginate hydrogel. Our study suggests that adopting toroid geometry in designing therapeutic microtissues potentially reduces mass loss of cellular grafts and thereby may improve the performance of transplanted islets towards a clinically viable cure for Type 1 diabetes. STATEMENT OF SIGNIFICANCE: Transplantation of therapeutic cells is a promising strategy for the treatment of a wide range of hormone or protein-deficiency diseases. However, the clinical application of this approach is hindered by the loss of cell viability and function at the avascular transplantation site. To address this challenge, we fabricated hydrogel-encapsulated islet-like microtissues with non-spheroidal geometry and optimal surface-to-volume ratio. This study demonstrated that the viability of therapeutic cells can be significantly increased solely by redesigning the microtissue configuration without requiring any additional biochemical or operational accessories. This study suggests that the adoption of toroid geometry provides a possible avenue to improve the long-term survival of transplanted therapeutic cells and expedite the translation of cell-based therapy towards clinical application.

Development of a hybrid peptide dendrimer micellar carrier system and its application in the reformulation of a hydrophobic therapeutic agent derived from traditional Chinese medicine.

The discovery that a cane toad poison-derived steroid, bufalin can significantly impact cancer cell proliferation supports its potential use in cancer therapy. However, its poor aqueous solubility and tissue deposition characteristics hamper its broader application as an anticancer therapeutic agent in its own right. To address this we developed an amphiphilic dendrimer-based delivery system, which self-assembles into discrete micelles in an aqueous environment. The bufalin-micelle inclusion complex was prepared by the co-precipitation method and their presence was confirmed by dynamic light scattering (DLS), zeta potential and differential scanning calorimetry (DSC) and transmission electron microscopy (TEM) measurements. The self-assembled bufalin-containing micelles were found to form at/above the dendrimer concentration of 105.38 µmol L-1, and showed a more than threefold increase in the aqueous solubility (142.9 µg mL-1) of bufalin, when compared with a saturated bufalin aqueous solution (42.4 µg mL-1), and two non-assembling peptides of similar composition (79.3 and 62.5 µg mL-1 respectively).

Self-assembling asymmetric peptide-dendrimer micelles - a platform for effective and versatile in vitro nucleic acid delivery.

Despite advancements in the development of high generation cationic-dendrimer systems for delivery of nucleic acid-based therapeutics, commercially available chemical agents suffer from major drawbacks such as cytotoxicity while being laborious and costly to synthesize. To overcome the aforementioned limitations, low-generation cationic peptide asymmetric dendrimers with side arm lipid (cholic and decanoic acid) conjugation were designed, synthesized and systematically screened for their ability to self-assemble into micelles using dynamic light scattering. Cytotoxicity profiling revealed that our entire asymmetric peptide dendrimer library when trialled alone, or as asymmetric dendrimer micelle-nucleic acid complexes, were non-cytotoxic across a broad concentration range. Further, the delivery efficiency of asymmetric peptide dendrimers in H-4-II-E (rat hepatoma), H2K (mdx mouse myoblast), and DAOY (human medulloblastoma) cells demonstrated that cholic acid-conjugated asymmetric dendrimers possess far superior delivery efficiency when compared to the commercial standards, Lipofectamine 2000 or Lipofectin®.

Bioprecursor prodrugs: molecular modification of the active principle.

A large number of therapeutic medications have undesirable properties that may generate pharmacological, pharmaceutical, or pharmacokinetic barriers in clinical drug applications. Metabolism of drugs by Phase-I & Phase-II metabolic pathways for possibility of active metabolites, which could in turn useful for rational designing of bioprecursor prodrugs of the active principle of interest. This review summarizes various approaches & development of drugs, namely bioprecursor prodrugs and active metabolites related to bioprecursor prodrugs.

Oseltamivir: a first line defense against swine flu.

Oseltamivir (has known by its brand name 'Tamiflu') is a prodrug, requiring ester hydrolysis for conversion to the active form, Oseltamivir carboxylate. Oseltamivir was the first orally active neuraminidase inhibitor commercially developed by US based Gilead Sciences and is currently marketed by F. Hoffmann-La Roche (Roche). Oseltamivir is an antiviral drug which works by blocking the function of the viral neuraminidase protein. US FDA approved Oseltamivir for prophylaxis of uncomplicated influenza A and B. Currently, Oseltamivir is the only first line defense drug available for the treatment of Swine Flu. Orally Oseltamivir is well tolerated and effective in treatment of influenza in adolescents and adults, including the elderly and patients with chronic cardiac and/or respiratory disease. Many of the pharmaceutical companies targeted Oseltamivir as a block buster molecule. In present review, we have tried to cover chemistry, mode of binding, total synthesis, current patent status, adverse effect and clinical status of Oseltamivir giving emphasis on medicinal chemistry aspect.

Rheumatoid arthritis: a new challenge in coming era.

Rheumatoid arthritis (RA) is mainly an auto-immune disease characterized by inflammation in joints. 1 in 50 people develop RA at some stage and at any age. This review summarizes the etiology, pathophysiology, risk factor, and treatment related to RA. The emphasis has been laid in particular on the new potential biological targets and the possible treatment as well as the current ongoing research status on RA.

Pharmacology and chemistry of diabetes mellitus and antidiabetic drugs: a critical review.

Diabetes mellitus, an epidemic metabolic disorders characterized by high blood glucose level associated with various macrovascular and microvascular complications, is one of the main causes of human suffering across the globe. Researchers around the world mainly focused on insulin, insulin analogues, oral hypoglycemic agents and various other complementary and alternate medicines to control the blood glucose levels in diabetes. The present review summarizes the disorders associated with elevation of blood glucose level, biochemical & endocrinological aspects and the current strategies to control. The emphasis has been laid in particular on the new potential biological targets and the possible treatment as well as the current ongoing research status on new generation hypoglycemic agents.