Fluorescence studies of short self-assemblying peptides

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Biobetters From an Integrated Computational/Experimental Approach

Biobetters are new drugs designed from existing peptide or protein-based therapeutics by improving their properties such as affinity and selectivity for the target epitope, and stability against degradation. Computational methods can play a key role in such design problems—by predicting the changes that are most likely to succeed, they can drastically reduce the number of experiments to be performed. Here we discuss the computational and experimental methods commonly used in drug design problems, focusing on the inverse relationship between the two, namely, the more accurate the computational predictions means the less experimental effort is needed for testing. Examples discussed include efforts to design selective analogs from toxin peptides targeting ion channels for treatment of autoimmune diseases and monoclonal antibodies which are the fastest growing class of therapeutic agents particularly for cancers and autoimmune diseases. Keywords: Rational drug design, Molecular dynamics, Docking, Potential of mean force, Free energy perturbatio

Vaccines and vaccination: history and emerging issues.

Prophylactic vaccines are crucial in modern healthcare and have been used successfully to combat bacterial and viral infectious diseases. Infections like polio and smallpox, which were dreaded historically, and which devastated the human race over many centuries, are now rare. Smallpox has been eradicated completely and polio is nearly eradicated because of vaccines. Vaccines differ fundamentally from other classes of medicines in that they are usually administered as a preventive measure to a healthy individual rather than to a sick person already with an infection, although exceptions to this practice exist. Most currently used prophylactic vaccines are based on established platforms, but many vaccine candidates, in late development stages, including several COVID-19 vaccines, use highly novel vaccine platforms not available historically. History of infectious diseases and prophylactic vaccines are filled with important scientific lessons, and thus provide valuable insights for the future. With hindsight, historically there were some ethically questionable approaches to testing vaccines and the germ warfare against native populations in the Americas and other regions. In this review, we examine key historical lessons learned with prophylactic vaccines with reflections on current healthcare dilemmas and controversies with respect to influenza and COVID-19 vaccines

Synthesis and enhanced cellular uptake in vitro of anti-HER2 multifunctional gold nanoparticles

Nanoparticle carriers offer the possibility of enhanced delivery of therapeutic payloads in tumor tissues due to tumor-selective accumulation through the enhanced permeability and retention effect (EPR). Gold nanoparticles (AuNP), in particular, possess highly appealing features for development as nanomedicines, such as biocompatibility, tunable optical properties and a remarkable ease of surface functionalization. Taking advantage of the latter, several strategies have been designed to increase treatment specificity of gold nanocarriers by attaching monoclonal antibodies on the surface, as a way to promote selective interactions with the targeted cells—an approach referred to as active-targeting. Here, we describe the synthesis of spherical gold nanoparticles surface-functionalized with an anti-HER2 antibody-drug conjugate (ADC) as an active targeting agent that carries a cytotoxic payload. In addition, we enhanced the intracellular delivery properties of the carrier by attaching a cell penetrating peptide to the active-targeted nanoparticles. We demonstrate that the antibody retains high receptor-affinity after the structural modifications performed for drug-conjugation and nanoparticle attachment. Furthermore, we show that antibody attachment increases cellular uptake in HER2 amplified cell lines selectively, and incorporation of the cell penetrating peptide leads to a further increase in cellular internalization. Nanoparticle-bound antibody-drug conjugates retain high antimitotic potency, which could contribute to a higher therapeutic index in high EPR tumors

Monoclonal antibody therapy of solid tumors: clinical limitations and novel strategies to enhance treatment efficacy

Monoclonal antibodies (mAbs) have become a cornerstone in the therapeutic guidelines of a wide range of solid tumors. The targeted nature of these biotherapeutics has improved treatment outcomes by offering enhanced specificity to reduce severe side effects experienced with conventional chemotherapy. Notwithstanding, poor tumor tissue penetration and the heterogeneous distribution achieved therein are prominent drawbacks that hamper the clinical efficacy of therapeutic antibodies. Failure to deliver efficacious doses throughout the tumor can lead to treatment failure and the development of acquired resistance mechanisms. Comprehending the morphological and physiological characteristics of solid tumors and their microenvironment that affect tumor penetration and distribution is a key requirement to improve clinical outcomes and realize the full potential of monoclonal antibodies in oncology. This review summarizes the essential architectural characteristics of solid tumors that obstruct macromolecule penetration into the targeted tissue following systemic delivery. It further describes mechanisms of resistance elucidated for blockbuster antibodies for which extensive clinical data exists, as a way to illustrate various modes in which cancer cells can overcome the anticancer activity of therapeutic antibodies. Thereafter, it describes novel strategies designed to improve clinical outcomes of mAbs by increasing potency and/or improving tumor delivery; focusing on the recent clinical success and growing clinical pipeline of antibody-drug conjugates, immune checkpoint inhibitors and nanoparticle-based delivery systems

Advances and Limitations of Antibody Drug Conjugates for Cancer

The popularity of antibody drug conjugates (ADCs) has increased in recent years, mainly due to their unrivalled efficacy and specificity over chemotherapy agents. The success of the ADC is partly based on the stability and successful cleavage of selective linkers for the delivery of the payload. The current research focuses on overcoming intrinsic shortcomings that impact the successful development of ADCs. This review summarizes marketed and recently approved ADCs, compares the features of various linker designs and payloads commonly used for ADC conjugation, and outlines cancer specific ADCs that are currently in late-stage clinical trials for the treatment of cancer. In addition, it addresses the issues surrounding drug resistance and strategies to overcome resistance, the impact of a narrow therapeutic index on treatment outcomes, the impact of drug–antibody ratio (DAR) and hydrophobicity on ADC clearance and protein aggregation

A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer

Antibody-drug conjugates (ADCs) have demonstrated a great therapeutic potential against cancer due to their target specificity and cytotoxicity. To exert a maximum therapeutic effect on cancerous cells, we have conjugated two different payloads to different amino acids, cysteines (cys) and lysines (lys), on trastuzumab, which is a humanised anti-HER2 monoclonal antibody. First, trastuzumab was conjugated with monomethyl auristatin E (MMAE), an antimitotic agent, through a cleavable linker (Val-Cit) to prepare ADC (Tmab-VcMMAE). Then, the ADC (Tmab-VcMMAE) was conjugated with a second antimitotic agent, Mertansine (DM1), via a non-cleavable linker Succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) to form a dual conjugate (Tmab-VcMMAE-SMCC-DM1). Our results indicated that the dual-payload conjugate, Tmab-VcMMAE-SMCC-DM1, had a synergistic and superior cytotoxic effect compared to trastuzumab alone. Ultimately employing a dual conjugation approach has the potential to overcome treatment-resistance and tumour recurrences and could pave the way to employ other payloads to construct dual (or multiple) payload complexes

Biologics and Vaccines for Nasal and Pulmonary Drug Delivery

Biologics are a rapidly emerging class of therapeutics that have succeeded clinically and commercially due to their specificity and efficacy against various diseases including cancer, inflammatory, and autoimmune diseases. Even though most biologics are administered parenterally, nasal and pulmonary delivery would be beneficial due to numerous advantages such as being patient-friendly, noninvasive, cost-effective, and less toxic. While there are currently a few nasal and inhaled biologics on the market, for example, Suprefact®, Minirin®, Miacalcin®, most of them are designed to treat ailments related to prostate carcinoma, diabetes, osteoporosis but not for respiratory diseases. Moreover, there are some marketed nasally delivered vaccines such as Flumist® and Nasovac-S® against influenza virus, inhaled vaccines that did not make it to market. Given the rise of respiratory infections such as MERS, SARS, and SARS-CoV-2, a great deal of interest exists in developing nasal and pulmonary-delivered biologics and vaccines for respiratory diseases. The objective of this chapter is to describe the potential for pulmonary and nasal delivery of biologics. Each section delves into introducing biologics and vaccines, followed by a portrayal of recent updates on nasal and pulmonary delivery of biologics and vaccines. The most promising formulation strategies for enhancing the stability and therapeutic efficacy of biologics as a part of research and development will be discussed