Pharmacokinetics and toxicity considerations for antibody-drug conjugates: an overview.

Antibody-drug conjugates (ADCs) is one of the fastest-growing drug-delivery systems. It involves a monoclonal antibody conjugated with payload via a ligand that directly targets the expressive protein of diseased cell. Hence, it reduces systemic exposure and provides site-specific delivery along with reduced toxicity. Because of this advantage, researchers have gained interest in this novel system. ADCs have displayed great promise in drug delivery and biomedical applications. However, a lack of understanding exists on their mechanisms of biodistribution, metabolism and side effects. To gain a better understanding of the therapeutics, careful consideration of the pharmacokinetics and toxicity needs to be undertaken. In this review, different pharmacokinetics parameters including distribution, bioanalysis and heterogeneity are discussed for developing novel therapeutics.

Greening of human-dominated ecosystems in India.

Satellite data show the Earth has been greening and identify croplands in India as one of the most prominent greening hotspots. Though India's agriculture has been dependent on irrigation enhancement to reduce crop water stress and increase production, the spatiotemporal dynamics of how irrigation influenced the satellite observed greenness remains unclear. Here, we use satellite-derived leaf area data and survey-based agricultural statistics together with results from state-of-the-art Land Surface Models (LSM) to investigate the role of irrigation in the greening of India's croplands. We find that satellite observations provide multiple lines of evidence showing strong contributions of irrigation to significant greening during dry season and in drier environments. The national statistics support irrigation-driven yield enhancement and increased dry season cropping intensity. These suggest a continuous shift in India's agriculture toward an irrigation-driven dry season cropping system and confirm the importance of land management in the greening phenomenon. However, the LSMs identify CO2 fertilization as a primary driver of greening whereas land use and management have marginal impacts on the simulated leaf area changes. This finding urges a closer collaboration of the modeling, Earth observation, and land system science communities to improve representation of land management in the Earth system modeling.

A Charge Variant of Bevacizumab Offers Enhanced FcRn-Dependent Pharmacokinetic Half-Life and Efficacy.

BACKGROUND: Lysine variants of monoclonal antibodies (mAbs) result from incomplete clipping of the C-terminal lysine residues of the heavy chain. Although the structure of the lysine variants has been determined for several mAb products, a detailed study that investigates the impact of lysine charge variants on PK/PD and preclinical safety is yet to be published. OBJECTIVE: An in-depth investigation of the impact of C- terminal lysine clipping of mAbs on safety and efficacy for bevacizumab charge variants. METHOD: Charge variant isolation using semi-preparative chromatography is followed by a comparative analysis of FcRn binding, pharmacokinetics, and pharmacodynamics in relevant animal models. RESULTS: K1 variant exhibited improved FcRn binding affinity (4-fold), half-life (1.3-fold), and anti-tumor activity (1.3-fold) as compared to the K0 (main) product. However, the K2 variant, even though exhibited higher FcRn affinity (2-fold), displayed lower half-life (1.6-fold) and anti-tumor activity at medium and low doses. Differential proteomic analysis revealed that seven pathways (such as glycolysis, gluconeogenesis, carbon metabolism, synthesis of amino acids) were significantly enriched. Higher efficacy of the K1 variant is likely due to higher bioavailability of the drug, leading to complete downregulation of the pathways that facilitate catering of the energy requirements of the proliferating tumor cells. On the contrary, the K2 variant exhibits a shorter half-life, resulting only in partial reduction in the metabolic/energy requirements of the growing tumor cells. CONCLUSION: Overall, we conclude that the mAb half-life, dosage, and efficacy of a biotherapeutic product are significantly impacted by the charge variant profile of a biotherapeutic product.

Recent advances in nanoparticles mediated photothermal therapy induced tumor regression.

Photothermal therapy (PTT) is a minimally invasive procedure for treating cancer. The two significant prerequisites of PTT are the photothermal therapeutic agent (PTA) and near-infrared radiation (NIR). The PTA absorbs NIR, causing hyperthermia in the malignant cells. This increased temperature at the tumor microenvironment finally results in tumor cell damage. Nanoparticles play a crucial role in PTT, aiding in the passive and active targeting of the PTA to the tumor microenvironment. Through enhanced permeation and retention effect and surface-engineering, specific targeting could be achieved. This novel delivery tool provides the advantages of changing the shape, size, and surface attributes of the carriers containing PTAs, which might facilitate tumor regression significantly. Further, inclusion of surface engineering of nanoparticles is facilitated through ligating ligands specific to overexpressed receptors on the cancer cell surface. Thus, transforming nanoparticles grants the ability to combine different treatment strategies with PTT to enhance cancer treatment. This review emphasizes properties of PTAs, conjugated biomolecules of PTAs, and the combinatorial techniques for a better therapeutic effect of PTT using the nanoparticle platform.

Stimuli-responsive In situ gelling system for nose-to-brain drug delivery.

The diagnosis and treatment of neurological ailments always remain an utmost challenge for research fraternity due to the presence of BBB. The intranasal route appeared as an attractive and alternative route for brain targeting of therapeutics without the intrusion of BBB and GI exposure. This route directly and effectively delivers the therapeutics to different regions of the brain via olfactory and trigeminal nerve pathways. However, shorter drug retention time and mucociliary clearance curtail the efficiency of the intranasal route. The in situ mucoadhesive gel overthrow the limitations of direct nose-to-brain delivery by not only enhancing nasal residence time but also minimizing the mucociliary clearance and enzymatic degradation. This delivery system further improves the nasal absorption as well as bioavailability of drugs in the brain. The in situ mucoadhesive gel is a controlled and sustained release system that facilitates the absorption of various proteins, peptides and other larger lipophilic and hydrophilic moieties. Owing to multiple benefits, in situ gelling system has been widely explored to target the brain via nasal route. However, very few review works are reported which explains the application of in situ nasal gel for brain delivery of CNS acting moieties. Hence, in this piece of work, we have initially discussed the global statistics of neurological disorders reported by WHO and other reputed organizations, nasal anatomy, mechanism and challenges of nose-to-brain drug delivery. The work mainly focused on the use of different stimuli-responsive polymers, specifically thermoresponsive, pH-responsive, and ion triggered systems for the development of an effective and controlled dosage form, i.e., in situ nasal gel for brain targeting of bioactives. We have also highlighted the origin, structure, nature and phase transition behavior of the smart polymers found suitable for nasal administration, including poloxamer, chitosan, EHEC, xyloglucan, Carbopol, gellan gum and DGG along with their application in the treatment of neurological disorders. The article is aimed to gather all the information of the past 10 years related to the development and application of stimuli-responsive in situ nasal gel for brain drug delivery.

Recent advances of gold nanoparticles as biomaterial in dentistry.

Major goal of dental treatment is to eradicate the existing diseases of the oral cavity and implement preventive measures to control the spread of the diseases. Various interventions are being used to cure the dental diseases. Due to the nanostructures, high surface volume and biocompatibility, Gold nanoparticles (GNPs) have been experimented in the treatment of gum diseases, dental caries, tissue engineering, dental implantology and diagnosis of cancers. GNPs possess antifungal and antibacterial activity, hence are incorporated in various biomaterials to potentiate the effect. They also enhance the mechanical properties of materials leading to improved outcomes. They are available in different sizes and concentrations to exhibits its beneficial outcomes. These properties of GNPs make these materials as choice of fillers in biomaterials. This review aims to discuss the effect of incorporation of GNPs in several biomaterials used for dental and medical applications.

Graphene nanosheets as reinforcement and cell-instructive material in soft tissue scaffolds.

Mechanical strength of polymeric scaffolds deteriorates quickly in the physiological mileu. This can be minimized by reinforcing the polymeric matrix with graphene, a planar two-dimensional material with unique physicochemical and biological properties. Association between the sheet and polymer chains offers a range of porosity commensurate with tissue requirements. Besides, studies suggest that corrugated structure of graphene offers desirable bio-mechanical cues for tissue regeneration. This review covers three important aspects of graphene-polymer composites, (a) the opportunity on reinforcing the polymer matrix with graphene, (b) challenges associated with limited aqueous processability of graphene, and (c) physiological signaling in the presence of graphene. Among numerous graphene materials, our discussion is limited to graphene oxide (GO) and reduced graphene oxide (rGO) nanosheets. Challenges associated with limited dispersity of hydrophobic sheets within the polymeric matrix have been discussed at molecular level.

Theranostic application of nanoemulsions in chemotherapy.

Theranostics has the potential to revolutionize the diagnosis, treatment, and prognosis of cancer, where novel drug delivery systems could be used to detect the disease at an early stage with instantaneous treatment. Various preclinical approaches of nanoemulsions with entrapped contrast and chemotherapeutic agents have been documented to act specifically on the tumor microenvironment (TME) for both diagnostic and therapeutic purposes. However, bringing these theranostic nanoemulsions through preclinical trials to patients requires several fundamental hurdles to be overcome, including the in vivo behavior of the delivery tool, degradation, and clearance from the system, as well as long-term toxicities. Here, we discuss recent advances in the application of nanoemulsions in molecular imaging with simultaneous therapeutic efficacy in a single delivery system.

Uncovering the Diversification of Tissue Engineering on the Emergent Areas of Stem Cells, Nanotechnology and Biomaterials.

Damaged or disabled tissue is life-threatening due to the lack of proper treatment. Many conventional transplantation methods like autograft, iso-graft and allograft are in existence for ages, but they are not sufficient to treat all types of tissue or organ damages. Stem cells, with their unique capabilities like self-renewal and differentiate into various cell types, can be a potential strategy for tissue regeneration. However, the challenges like reproducibility, uncontrolled propagation and differentiation, isolation of specific kinds of cell and tumorigenic nature made these stem cells away from clinical application. Today, various types of stem cells like embryonic, fetal or gestational tissue, mesenchymal and induced-pluripotent stem cells are under investigation for their clinical application. Tissue engineering helps in configuring the stem cells to develop into a desired viable tissue, to use them clinically as a substitute for the conventional method. The use of stem cell-derived Extracellular Vesicles (EVs) is being studied to replace the stem cells, which decreases the immunological complications associated with the direct administration of stem cells. Tissue engineering also investigates various biomaterials to use clinically, either to replace the bones or as a scaffold to support the growth of stemcells/ tissue. Depending upon the need, there are various biomaterials like bio-ceramics, natural and synthetic biodegradable polymers to support replacement or regeneration of tissue. Like the other fields of science, tissue engineering is also incorporating the nanotechnology to develop nano-scaffolds to provide and support the growth of stem cells with an environment mimicking the Extracellular matrix (ECM) of the desired tissue. Tissue engineering is also used in the modulation of the immune system by using patient-specific Mesenchymal Stem Cells (MSCs) and by modifying the physical features of scaffolds that may provoke the immune system. This review describes the use of various stem cells, biomaterials and the impact of nanotechnology in regenerative medicine.

Derivatization approaches and applications of pullulan.

Pullulan (PUL), a linear exo-polysaccharide, is useful in industries as diverse as food, cosmetics and pharmaceuticals. PUL presents many favorable characteristics, such as renewable origin, biocompatibility, stability, hydrophilic nature, and availability of reactive sites for chemical modification. With an inherent affinity to asialoglycoprotein receptors, PUL can be used for targeted drug delivery to the liver. Besides, these primary properties have been combined with modern synthetic approaches for developing multifunctional biomaterials. This is evident from numerous studies on approaches, such as hydrophobic modification, cross-linking, grafting and transformation as a polyelectrolyte. In this review, we have discussed up-to-date advances on chemical modifications and emerging applications of PUL in targeted theranostics and tissue engineering. Besides, we offer an overview of its applications in food, cosmetics and environment remediation.

Recent Biomedical Applications on Stem Cell Therapy: A Brief Overview.

Stem cells are the specialized cell population with unique self-renewal ability and act as the precursor of all the body cells. Broadly, stem cells are of two types one is embryonic stem cells while the other is adult or somatic stem cells. Embryonic stem cells are the cells of zygote of the blastocyst which give rise to all kind of body cells including embryonic cells, and it can reconstruct a complete organism. While the adult stem cells have limited differentiation ability in comparison with embryonic stem cells and it proliferates into some specific kind of cells. This unique ability of the stem cell makes it a compelling biomedical and therapeutic tool. Stem cells primarily serve as regenerative medicine for particular tissue regeneration or the whole organ regeneration in any physical injury or disease condition (like diabetes, cancer, periodontal disorder, etc.), tissue grafting and plastic surgery, etc. Along with this, it is also used in various preclinical and clinical investigations, biomedical engineering and as a potential diagnostic tool (such as the development of biomarkers) for non-invasive diagnosis of severe disorders. In this review article, we have summarized the application of stem cell as regenerative medicine and in the treatment of various chronic diseases.

Microsponge: An emerging drug delivery strategy.

Microsponges are the spherical particles ranging from 5 to 300 µm in size. These are further made up of clusters of smaller spheres. They are designed for delivering the drug efficiently at a comparatively lesser dose and enhancing the stability, modifying the drug release profile and minimizing the side effects. Microsponge drug delivery system decrease transdermal invasion of the active ingredient into the skin while increasing the time the drug remains on the skin surface or within the epidermis. Preparation of the microsponges includes two techniques: Liquid-liquid suspension polymerization and Quasi-emulsion solvent diffusion method. Their characterization and evaluation can be done in many ways like particle-size measurement and porosity, morphology, true density determination, analyzing the rheological properties, and dissolution studies. Present work focuses on the detailed study of the microsponge drug delivery system. This will help the reader to get all the information regarding the microsponge delivery systems.

New chiral reverse phase HPLC method for enantioselective analysis of ketorolac using chiral AGP column.

A simple, specific, precise, sensitive and rapid reverse phase-HPLC method was developed for determination of ketorolac enantiomers, a potent nonnarcotic analgesic in pharmaceutical formulations. The method was developed on a chiral AGP column. Mobile phase was 0.1 M sodium phosphate buffer (pH 4.5): Isopropanol (98:2, v/v), at a flow rate of 1 mL/min with run time of 15 min. Ultraviolet detection was made at 322 nm. The linearity range was 0.02-10 µg/mL for each of the enantiomers. The mobile phase composition was systematically studied to find the optimum chromatographic conditions. Validation of the method under the conditions selected showed that it was selective and precise and that the detector response was linear function of ketorolac.