Molecular Pharmaceutics

Ternary amorphous solid dispersions (ASDs) consist of a multicomponent carrier with the aim of improving physical stability or dissolution performance. A polymer blend as a carrier that combines a water-insoluble and a water-soluble polymer may delay the drug release rate, minimizing the risk of precipitation from the supersaturated state. Different microstructures of the ternary ASD may result in different drug release performances; hence, understanding the phase morphology of the polymer blend is crucial prior to drug incorporation...

Using the time-temperature-transformation diagrams, we demonstrated a correlation between molecular mobility and crystallization in amorphous solid dispersions of nifedipine (NIF) with each polyvinylpyrrolidone vinyl acetate (PVPVA64) and polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus). The behavior was compared with the NIF dispersions prepared with each polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) [Lalge et al., Mol. Pharmaceutics 2023, 20 (3), 1806-1817]...

Melanoma is an aggressive skin cancer notorious for high levels of drug resistance. Additionally, current treatments such as immunotherapies are often associated with numerous adverse side effects. The use of nitric oxide (NO) may represent an attractive treatment for melanoma due to NO's various anticancer properties, unlikeliness to foster resistance, and limited toxicity toward healthy tissues. The anticancer effects of chemical NO donors have been explored previously but with limited understanding of the needed characteristics for exerting optimal antimelanoma activity...

Intracellular copper ion homeostasis has become an attractive target for cancer therapy. Herein, we report a 2,2'-dipicolylamine (DPA) functionalized polyglutamate derivative (PDHB) which is capable of rapidly forming PDHB-copper complex (PDHB@Cu) due to the strong coordination ability of pendant DPA with Cu2+ . High drug loading content of doxorubicin (DOX) (>30 wt %) is realized due to the strong affinity of Cu2+ to DOX, while that is about 10 wt % for PDHB without Cu2+ . The obtained PDHB@Cu-DOX can respond to specific endogenous stimuli (pH and glutathione (GSH)), releasing Cu2+ and DOX...

The proceedings from the 30th August 2023 (Day 2) of the workshop "Physiologically Based Biopharmaceutics Models (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives" are provided herein. Day 2 covered PBBM case studies from six regulatory authorities which provided considerations for model verification, validation, and application based on the context of use (COU) of the model. PBBM case studies to define critical material attribute (CMA) specification settings, such as active pharmaceutical ingredient (API) particle size distributions (PSDs) were shared...

Computational methods including machine learning and molecular dynamics simulations have strong potential to characterize, understand, and ultimately predict the properties of proteins relevant to their stability and function as therapeutics. Such methods would streamline the development pathway by minimizing the current experimental testing required for many protein variants and formulations. The molecular understanding of thermostability and aggregation propensity has advanced significantly along with predictive algorithms based on the sequence-level or structural-level information on a protein...

The particle drifting effect, where nanosized colloidal drug particles overcome the diffusional resistance of the aqueous boundary layer adjacent to the intestinal wall and increase drug absorption rates, is drawing increasing attention in pharmaceutical research. However, mechanistic understanding and accurate prediction of the particle drifting effect remain lacking. In this study, we systematically evaluated the extent of the particle drifting effect affected by drug and colloidal properties, including the size, number, and type of the moving species using biphasic diffusion experiments combined with computational fluid dynamics simulations and mass transport analyses...

Flavonoid-based organometallic complexes were revealed to be novel bioactive compounds. The taxifolin ruthenium- p -cymene nanoparticle (TaxRu-NPs) was produced in this study, and the toxicological assessment was done prior to in vivo chemotherapeutic research. Furthermore, the in vitro chemotherapeutic investigation used the A549 and NCI-H460 lung cancer cell lines. The in vitro study found that TaxRu-NPs induced apoptosis in lung cancer cells and hindered their ability to form colonies and migrate. The in vivo study showed that treatment with TaxRu-NPs restored the histological structure of a normal lung with less hyperplasia and lymphocytic infiltration...

Lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines have been approved for use to combat coronavirus disease 2019 (COVID-19). The mRNA-LNPs contain PEG-conjugated lipids. Clinical studies have reported that mRNA-LNPs induce the production of anti-PEG antibodies, but the anti-PEG antibodies do not affect the production of neutralizing antibodies. However, the detailed influence of anti-PEG antibodies on mRNA-LNP vaccines remains unclear. Therefore, in this study, we prepared ovalbumin (OVA) as a model antigen-encoding mRNA-loaded LNP (mRNA-OVA-LNP), and we determined whether anti-PEG antibodies could affect the antigen-specific immune response of mRNA-OVA-LNP vaccination in mice pretreated with PEG-modified liposomes to induce the production of anti-PEG antibodies...

The blood-brain barrier (BBB) is a highly selective network of various cell types that acts as a filter between the blood and the brain parenchyma. Because of this, the BBB remains a major obstacle for drug delivery to the central nervous system (CNS). In recent years, there has been a focus on developing various modifiable platforms, such as monoclonal antibodies (mAbs), nanobodies (Nbs), peptides, and nanoparticles, as both therapeutic agents and carriers for targeted drug delivery to treat brain cancers and diseases...

Given the aging populations in advanced countries globally, many pharmaceutical companies have focused on developing central nervous system (CNS) drugs. However, due to the blood-brain barrier, drugs do not easily reach the target area in the brain. Although conventional screening methods for drug discovery involve the measurement of (unbound fraction of drug) brain-to-plasma partition coefficients, it is difficult to consider nonequilibrium between plasma and brain compound concentration-time profiles. To truly understand the pharmacokinetics/pharmacodynamics of CNS drugs, compound concentration-time profiles in the brain are necessary; however, such analyses are costly and time-consuming and require a significant number of animals...

B7-H3 has emerged as a promising target and potential biomarker for diagnosing tumors, evaluating treatment efficacy, and determining patient prognosis. Hu4G4 is a recombinant humanized antibody that selectively targets the extracellular domain of human B7-H3. In this study, we describe the radiolabeling of hu4G4 with the positron emission tomography (PET) emitter radionuclide zirconium 89 (89 Zr) and evaluate its potency as an immuno-PET tracer for B7-H3-targeted imaging by comparing it in vitro and in vivo to [89 Zr]Zr-DFO-DS-5573a using various models...

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Heat shock protein 90 (Hsp90) is a promising target for cancer therapy and imaging. Accurate detection of Hsp90 levels in tumors via noninvasive PET imaging might be beneficial for management. To achieve this, the precursor compound Dimer-Sansalvamide A (Dimer-San A) was PEGylated and modified by conjugating it with the bifunctional chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The 18 F-labeled PEGylated Dimer-SanA decapeptide (18 F-PEGylated San A) was completed within 30 min using a two-step process...

Zotizalkib (TPX-0131), a fourth-generation macrocyclic anaplastic lymphoma kinase (ALK) inhibitor, is designed to overcome resistance due to secondary ALK mutations in non-small cell lung cancer (NSCLC). We here evaluated the pharmacokinetic roles of the ABCB1 (P-gp/MDR1) and ABCG2 (BCRP) efflux transporters, OATP1 influx transporters and the metabolizing enzymes CES1 and CYP3A in plasma and tissue disposition of zotizalkib after oral administration in relevant mouse models. Zotizalkib was efficiently transported by hABCB1 in vitro...

Biorelevant dissolution and its concept have been widely accepted and further developed to meaningfully predict the bioperformance of oral drug products. Biorelevant methodologies have been applied to design and optimize oral formulations, to facilitate formulation bridging, and to predict the outcome of bioperformance by coupling the results with modeling. Yet, those methodologies have often been independently customized to align with specific aspects of the oral drug products being developed. Therefore, the evolution of biorelevant dissolution methodologies has taken slightly diverse pathways rather than being standardized like compendial quality control (QC) methodologies...

Abnormalities in the RAS-RAF signaling pathway occur in many solid tumors, leading to aberrant tumor proliferation, invasion, and metastasis. Due to the elusive pharmacology of RAS, RAF inhibitors have become the main targeted therapeutic drugs. Naporafenib (LXH-254) is a high-affinity pan-RAF inhibitor with FDA Fast Track Qualification. We sought to develop an 18 F-labeled molecular probe from LXH-254 for PET imaging of tumors overexpressing RAF to noninvasively screen patients for susceptibility to targeted RAF therapy...

In recent years, carbon monoxide (CO) has garnered increased attention as a novel green therapy for hepatocellular carcinoma (HCC) treatment. However, the CO donor is still limited in clinical application due to its lack of targeted ability and unstable release rate. Here, self-assembled amphiphilic nanomicelles glucose-polyethylene glycol (PEG)-lipoic acid (LA)-Fe2 (CO)6 (Glu-Fe2 (CO)6 ) are first designed as a CO donor and synthesized via a chemical method, combining glucose with Fe2 (CO)6 through PEG-LA...

Aggressive glioma exhibits a poor survival rate. Increased tumor aggression is linked to both tumor cells and tumor-associated macrophages (TAMs), which induce pro-aggression, invasion, and metastasis. Imperatively, for effective treatment, it is important to target both glioma cells and TAMs. Haloperidol, a neuropsychotic drug, avidly targets the sigma receptor (SR), which is expressed in higher levels in both the cell types. Herein, we present the development of a novel cationic lipid-conjugated reduced haloperidol (±RHPC8), which aims to mediate the SR-targeted antiglioma effect...

The specific expression of prostate-specific membrane antigen (PSMA) makes it an ideal target for the diagnosis and treatment of prostate cancer. Currently, many 99m Tc-labeled PSMA-targeted tracers have been developed. However, the high renal uptake of these 99m Tc-labeled tracers is a common problem that limits their clinical application. In this work, the ligand (EUKPG) using D Pro-Gly as the linker was synthesized and three 99m Tc-labeled complexes ([99m Tc]Tc-EUKPG-EDDA, [99m Tc]Tc-EUKPG-TPPTS, [99m Tc]Tc-EUKPG-TPPMS) with different coligands were prepared and evaluated...