Immune checkpoint-targeted antibodies: a room for dose and schedule optimization?

Anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint inhibitors are therapeutic monoclonal antibodies that do not target cancer cells but are designed to reactivate or promote antitumor immunity. Dosing and scheduling of these biologics were established according to conventional drug development models, even though the determination of a maximum tolerated dose in the clinic could only be defined for anti-CTLA-4. Given the pharmacology of these monoclonal antibodies, their high interpatient pharmacokinetic variability, the actual clinical benefit as monotherapy that is observed only in a specific subset of patients, and the substantial cost of these treatments, a number of questions arise regarding the selected dose and the dosing interval. This review aims to outline the development of these immunotherapies and considers optimization options that could be used in clinical practice.

Chitosan Nanoparticle-Based System: A New Insight into the Promising Controlled Release System for Lung Cancer Treatment

Lung cancer has been recognized as one of the most often diagnosed and perhaps most lethal cancer diseases worldwide. Conventional chemotherapy for lung cancer-related diseases has bumped into various limitations and challenges, including non-targeted drug delivery, short drug retention period, low therapeutic efficacy, and multidrug resistance (MDR). Chitosan (CS), a natural polymer derived from deacetylation of chitin, and comprised of arbitrarily distributed β-(1-4)-linked d-glucosamine (deacetylated unit) and N-acetyl-d-glucosamine (acetylated unit) that exhibits magnificent characteristics, including being mucoadhesive, biodegradable, and biocompatible, has emerged as an essential element for the development of a nano-particulate delivery vehicle. Additionally, the flexibility of CS structure due to the free protonable amino groups in the CS backbone has made it easy for the modification and functionalization of CS to be developed into a nanoparticle system with high adaptability in lung cancer treatment. In this review, the current state of chitosan nanoparticle (CNP) systems, including the advantages, challenges, and opportunities, will be discussed, followed by drug release mechanisms and mathematical kinetic models. Subsequently, various modification routes of CNP for improved and enhanced therapeutic efficacy, as well as other restrictions of conventional drug administration for lung cancer treatment, are covered.

Novel Drug Delivery Systems and its Future Prospects

Most common methods of delivery include the preferred topical (skin), transmucosal (nasal, buccal, sublingual, vaginal, ocular and rectal) and inhalation routes. The conventional dosage forms provide drug release immediately and it causes fluctuation of drug level in blood depending upon dosage form. Therefore to maintain the drug concentration within therapeutically effective range needs novel drug delivery system. In the past few decades, considerable attention has been focused on the development of novel drug delivery system (NDDS). The NDDS should ideally fulfill two prerequisites. Firstly, it should deliver the drug at a rate directed by the needs of the body, over the period of treatment. Secondly, it should channel the active entity to the site of action. In conventional drug delivery systems, there is little or no control over release of the drug and effective concentration at the target site can be achieved by irregular administration of grossly excessive doses. At present, no available drug delivery system behaves ideally, but sincere attempts have been made to achieve them through various novel approaches in drug delivery.

Development of Pharmaceutical Nanomedicines: From the Bench to the Market

Nanotechnology plays a significant role in the field of medicine and in drug delivery, mainly due to the major limitations affecting the conventional pharmaceutical agents, and older formulations and delivery systems. The effect of nanotechnology on healthcare is already being felt, as various nanotechnology applications have been developed, and several nanotechnology-based medicines are now on the market. Across many parts of the world, nanotechnology draws increasing investment from public authorities and the private sector. Most conventional drug-delivery systems (CDDSs) have an immediate, high drug release after administration, leading to increased administration frequency. Thus, many studies have been carried out worldwide focusing on the development of pharmaceutical nanomedicines for translation into products manufactured by local pharmaceutical companies. Pharmaceutical nanomedicine products are projected to play a major role in the global pharmaceutical market and healthcare system. Our objectives were to examine the nanomedicines approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in the global market, to briefly cover the challenges faced during their development, and to look at future perspectives. Additionally, the importance of nanotechnology in developing pharmaceutical products, the ideal properties of nanocarriers, the reasons behind the failure of some nanomedicines, and the important considerations in the development of nanomedicines will be discussed in brief.

Nanoparticulate Drug Delivery Systems: An update

The paper is aimed to provide a comprehensive review on nanoparticles, methods of preparation, applications in drug delivery. In recent years, there has been an exponential interest within the development of novel drug delivery systems using nanoparticles. Nanoparticles offers significant advantages over the conventional drug delivery in terms of high stability, high specificity, high drug carrying capacity, ability for controlled release, possibility to use in several route of administration and therefore the capability to deliver both hydrophilic and hydrophobic drug molecules. This review focuses on classification, methods of preparation, characterization, application, advantages of nanoparticles and health perspectives.

A Review on Nanoparticles: Preparation and Characterization of Nanoparticles

The development of innovative medication delivery systems has increased at an exponential rate in the last few years. Nanoparticles are particles with a size of between one and one hundred nanometers. Nanoparticles provide substantial benefits over conventional drug administration in terms of high bioavailability, high stability, high drug-carrying capacity, and other characteristics. This review concentrated mostly on the classification of nanoparticles, the technique of synthesis, the evaluation of nanoparticles, and the list of FDA-approved nanomedicines now available on the market.

Nanocarrier-Based Approaches for the Efficient Delivery of Anti-Tubercular Drugs and Vaccines for Management of Tuberculosis

Drug-resistant species of tuberculosis (TB), which spread faster than traditiona TB, is a severely infectious disease. The conventional drug therapy used in the management of tuberculosis has several challenges linked with adverse effects. Hence, nanotherapeutics served as an emerging technique to overcome problems associated with current treatment. Nanotherapeutics helps to overcome toxicity and poor solubility issues of several drugs used in the management of tuberculosis. Due to their diameter and surface chemistry, nanocarriers encapsulated with antimicrobial drugs are readily taken up by macrophages. Macrophages play a crucial role as they serve as target sites for active and passive targeting for nanocarriers. The surface of the nanocarriers is coated with ligand-specific receptors, which further enhances drug concentration locally and indicates the therapeutic potential of nanocarriers. This review highlights tuberculosis’s current facts, figures, challenges associated with conventional treatment, different nanocarrier-based systems, and its application in vaccine development.

Microfluidics Technology for the Design and Formulation of Nanomedicines

In conventional drug administration, drug molecules cross multiple biological barriers, distribute randomly in the tissues, and can release insufficient concentrations at the desired pathological site. Controlling the delivery of the molecules can increase the concentration of the drug in the desired location, leading to improved efficacy, and reducing the unwanted effects of the molecules under investigation. Nanoparticles (NPs), have shown a distinctive potential in targeting drugs due to their unique properties, such as large surface area and quantum properties. A variety of NPs have been used over the years for the encapsulation of different drugs and biologics, acting as drug carriers, including lipid-based and polymeric NPs. Applying NP platforms in medicines significantly improves the disease diagnosis and therapy. Several conventional methods have been used for the manufacturing of drug loaded NPs, with conventional manufacturing methods having several limitations, leading to multiple drawbacks, including NPs with large particle size and broad size distribution (high polydispersity index), besides the unreproducible formulation and high batch-to-batch variability. Therefore, new methods such as microfluidics (MFs) need to be investigated more thoroughly. MFs, is a novel manufacturing method that uses microchannels to produce a size-controlled and monodispersed NP formulation. In this review, different formulation methods of polymeric and lipid-based NPs will be discussed, emphasizing the different manufacturing methods and their advantages and limitations and how microfluidics has the capacity to overcome these limitations and improve the role of NPs as an effective drug delivery system.

A Graph Convolutional Network-based screening strategy for rapid identification of SARS-CoV-2 cell-entry inhibitors

The cell entry of SARS-CoV-2 has emerged as an attractive drug development target. We previously reported that the entry of SARS-CoV-2 depends on the cell surface heparan sulfate proteoglycan (HSPG) and the cortex actin, which can be targeted by therapeutic agents identified by conventional drug repurposing screens. However, this drug identification strategy requires laborious library screening, which is time-consuming and often limited number of compounds can be screened. As an alternative approach, we developed and trained a graph convolutional network (GCN)-based classification model using information extracted from experimentally identified HSPG and actin inhibitors. This method allowed us to virtually screen 170,000 compounds, resulting in ~2000 potential hits. A hit confirmation assay with the uptake of a fluorescently labeled HSPG cargo further shortlisted 256 active compounds. Among them, 16 compounds had modest to strong inhibitory activities against the entry of SARS-CoV-2 pseudotyped particles into Vero E6 cells. These results establish a GCN-based virtual screen workflow for rapid identification of new small molecule inhibitors against validated drug targets.