J. Anand Subramony

Engineered in-situ depot-forming hydrogels for intratumoral drug delivery.

Chemotherapy is the traditional treatment for intermediate and late stage cancers. The search for treatment options with minimal side effects has been ongoing for several years. Drug delivery technologies that result in minimal or no side effects with improved ease of use for the patients are receiving increased attention. Polymer drug conjugates and nanoparticles can potentially offset the volume of drug distribution while enhancing the accumulation of the active drug in tumors thereby reducing side effects. Additionally, development of localized drug delivery platforms is being investigated as another key approach to target tumors with minimal or no toxicity. Development of in-situ depot-forming gel systems for intratumoral delivery of immuno-oncology actives can enhance drug bioavailability to the tumor site and reduce systemic toxicity. This field of drug delivery is critical to develop given the advent of immunotherapy and the availability of novel biological molecules for treating solid tumors. This article reviews the advances in the field of engineered in-situ gelling platforms as a practical tool for local delivery of active oncolytic agents to tumor sites.

Composite iron oxide–Prussian blue nanoparticles for magnetically guided T 1 -weighted magnetic resonance imaging and photothermal therapy of tumors

Theranostic nanoparticles offer the potential for mixing and matching disparate diagnostic and therapeutic functionalities within a single nanoparticle for the personalized treatment of diseases. In this article, we present composite iron oxide-gadolinium-containing Prussian blue nanoparticles (Fe3O4@GdPB) as a novel theranostic agent for T1-weighted magnetic resonance imaging (MRI) and photothermal therapy (PTT) of tumors. These particles combine the well-described properties and safety profiles of the constituent Fe3O4 nanoparticles and gadolinium-containing Prussian blue nanoparticles. The Fe3O4@GdPB nanoparticles function both as effective MRI contrast agents and PTT agents as determined by characterizing studies performed in vitro and retain their properties in the presence of cells. Importantly, the Fe3O4@GdPB nanoparticles function as effective MRI contrast agents in vivo by increasing signal:noise ratios in T1-weighted scans of tumors and as effective PTT agents in vivo by decreasing tumor growth rates and increasing survival in an animal model of neuroblastoma. These findings demonstrate the potential of the Fe3O4@GdPB nanoparticles to function as effective theranostic agents.

Improving drug-like properties of insulin and GLP-1 via molecule design and formulation and improving diabetes management with device & drug delivery ☆

&NA; There is an increased incidence of diabetes worldwide. The discovery of insulin revolutionized the management of diabetes, the revelation of glucagon‐like peptide‐1 (GLP‐1) and introduction of GLP‐1 receptor agonists to clinical practice was another breakthrough. Continued translational research resulted in better understanding of diabetes, which, in combination with cutting‐edge biology, chemistry, and pharmaceutical tools, have allowed for the development of safer, more effective and convenient insulins and GLP‐1. Advances in self‐administration of insulin and GLP‐1 receptor agonist therapies with use of drug‐device combination products have further improved the outcomes of diabetes management and quality of life for diabetic patients. The synergies of insulin and GLP‐1 receptor agonist actions have led to development of devices that can deliver both molecules simultaneously. New chimeric GLP‐1‐incretins and insulin‐GLP‐1‐incretin molecules are also being developed. The objective of this review is to summarize molecular designs to improve the drug‐like properties of insulin and GLP‐1 and to highlight the continued advancement of drug‐device combination products to improve diabetes management. Graphical abstract Figure. No caption available.

Submicron Aggregation of Chemically Denatured Monoclonal Antibody

Isothermal chemical denaturation (ICD) has been widely used to evaluate the conformational stability of therapeutic proteins such as monoclonal antibodies. However, the chemical unfolding pathway and the subsequent aggregation of antibodies are not yet well-understood. In the present work, we conducted a systematic study on an ICD-induced aggregation of a pharmaceutical monoclonal antibody. Using dynamic light scattering, we monitored formation and growth of submicron aggregates in various buffers. Our experiments revealed a nucleation-controlled submicron aggregation of the antibody in the presence of chemical denaturant. After the unfolded protein reached a steady state, we reduced the denaturant concentration by dilution or dialysis to trigger further aggregation after ICD. In this way, we studied the pH effect on aggregation of the stressed protein after removal of denaturant. The ICD-dilution experiment provides a practical means for studying the propensity of unfolded proteins to form aggregates under various formulation conditions. This unique method allows us to control the degree of protein unfolding and the initiation of post-ICD aggregation.

Oral peptide delivery: Translational challenges due to physiological effects

Abstract Oral delivery of peptide therapeutics as a convenient alternate to injections has been an area of research for the pharmaceutical scientific community for the last several decades. However, systemic delivery of therapeutic peptides via the oral route has been a daunting task due to the low pH denaturation of the peptides in the stomach, enzymatic instability, and poor transport across the tight junctions resulting in very low bioavailability. The low bioavailability is accompanied by large intra‐ and inter‐subject variability leading to translational issues, preventing the development of successful peptide therapeutics. The inter‐subject variability leads to large differences in pharmacologic responses in individuals and thus the dose required to produce therapeutic effect could vary between individuals making the development of drug product a very difficult task. A substantial amount of research has been (and continues to be) performed with a focus on getting acceptable absorption and reproducible results. Nonetheless, the high variability and low bioavailability during oral administration of peptides is still a work in progress and under‐explored in a systematic way. While there are several review articles and scattered publications that discuss potential technologies for oral peptide delivery, a detailed look into the physiological challenges and absorption barriers which are a hindrance to successful clinical translation, is lacking. Herein, we have analyzed the physiological barriers within the gastrointestinal (GI) tract that are the root causes for the low bioavailability and high variability of oral delivery of peptides in humans. In particular, we have taken a detailed look at the key influencing factors such as the nature of various GI tract parameters, components of the GI tract that influences the uptake, site of absorption, pH of the gastric and intestinal compartments, food effect, and role of peptidases in affecting oral peptide absorption. Lack of in vitro ‐ in vivo correlations and variability in animal models have also been highlighted as key impediments in understanding the challenges. The unique perspective presented herein for overcoming the physiological absorption barriers, will offer better developability approaches and will positively impact clinical translation of future oral peptide therapeutics. A deep understanding of these effects are vital, given the emergence of microbiome and oral biologic drug delivery that are fast emerging as the next wave of personalized patient centric therapies. Graphical abstract Figure. No Caption available.

Metastability Gap in the Phase Diagram of Monoclonal IgG Antibody

Crystallization of IgG antibodies has important applications in the fields of structural biology, biotechnology, and biopharmaceutics. However, a rational approach to crystallize antibodies is still lacking. In this work, we report a method to estimate the solubility of antibodies at various temperatures. We experimentally determined the full phase diagram of an IgG antibody. Using the full diagram, we examined the metastability gaps, i.e., the distance between the crystal solubility line and the liquid-liquid coexistence curve, of IgG antibodies. By comparing our results to the partial phase diagrams of other IgGs reported in literature, we found that IgG antibodies have similar metastability gaps. Thereby, we present an equation with two phenomenological parameters to predict the approximate location of the solubility line of IgG antibodies with respect to their liquid-liquid coexistence curves. We have previously shown that the coexistence curve of an antibody solution can be readily determined by the polyethylene glycol-induced liquid-liquid phase separation method. Combining the polyethylene glycol-induced liquid-liquid phase separation measurements and the phenomenological equation in this article, we provide a general and practical means to predict the thermodynamic conditions for crystallizing IgG antibodies in the solution environments of interest.