Development of a peptide-based tumor-activated checkpoint inhibitor for cancer immunotherapy.

Antibody-based checkpoint inhibitors have achieved great success in cancer immunotherapy, but their uncontrollable immune-related adverse events remain a major challenge. In this study, we developed a tumor-activated nanoparticle that is specifically active in tumors but not in normal tissues. We discovered a short anti-PD-L1 peptide that blocks the PD-1/PD-L1 interaction.

Kinetic sand! A tale of sandy times.

Kinetic magnetic sand, composed of ultra-fine sand and dimethicone in a 98%-2% ratio, is a versatile sensory toy known for its moldable properties and structural stability (1). Despite the name, it lacks actual magnetic features. Ingesting kinetic sand can pose risks, including choking and gastrointestinal issues, especially in young children.

Delivery of a STING Agonist Using Lipid Nanoparticles Inhibits Pancreatic Cancer Growth.

Introduction: The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive and characterized by a large number of cancer-associated fibroblasts, myeloid-derived suppressor cells, and regulatory T cells. Stimulator of interferon genes (STING) is an endoplasmic reticulum receptor that plays a critical role in immunity. STING agonists have demonstrated the ability to inflame the TME, reduce tumor burden, and confer anti-tumor activity in mouse models.

Impact of Propeptide Cleavage on the Stability and Activity of a Streptococcal Immunomodulatory C5a Peptidase for Biopharmaceutical Development.

Posttranslational modifications of proteins can impact their therapeutic efficacy, stability, and potential for pharmaceutical development. The Group AC5a peptidase (ScpA) is a multi-domain protein composed of an N-terminal signal peptide, a catalytic domain (including propeptide), three fibronectin domains, and cell membrane-associated domains. It is one of several proteins produced by Group Aknown to cleave components of the human complement system.

Inclusion Complex of Ibuprofen-β-Cyclodextrin Incorporated in Gel for Mucosal Delivery: Optimization Using an Experimental Design.

β-Cyclodextrin/ibuprofen inclusion complex was synthesized by freeze-drying method and characterized for phase solubility profiles, infrared spectra, thermal analysis, and X-ray powder diffractograms. The inclusion complex with HP-β-CD, as confirmed by molecular dynamics simulations, enhanced the aqueous solubility of ibuprofen by almost 30-fold compared to ibuprofen alone. Different grades of Carbopol (Carbopol 934P/Carbopol 974P/Carbopol 980 NF/Carbopol Ultrez 10 NF) and cellulose derivatives (HPMC K100M/HPMC K15M/HPMC K4M/HPMC E15LV/HPC) were evaluated for mucoadhesive gels incorporating the inclusion complex.

The development of a solid lipid nanoparticle (SLN)-based lacticin 3147 hydrogel for the treatment of wound infections.

Chronic wounds affect millions of people globally. This number is set to rise with the increasing incidence of antimicrobial-resistant bacterial infections, such as methicillin-resistant Staphylococcus aureus (MRSA), which impair the healing of chronic wounds. Lacticin 3147 is a two-peptide chain bacteriocin produced by Lactococcus lactis that is active against S.

Development of amino acid-modified biodegradable lipid nanoparticles for siRNA delivery.

The use of siRNA therapeutics to treat cancer is a very promising approach. However, specific delivery of siRNAs to tumors remains a major challenge. The recent success of siRNA delivery to the liver has incentivized the development of biomaterials for siRNA delivery into tumors.

Discovery of Cyclic Peptide Inhibitors Targeting PD-L1 for Cancer Immunotherapy.

Blockade of the interaction between programmed cell death ligand-1 (PD-L1) and its receptor PD-1 has shown great success in cancer immunotherapy. Peptides possess unique characteristics that give them significant advantages as immune checkpoint inhibitors. However, unfavorable physicochemical properties and proteolytic stability profiles limit the translation of bioactive peptides as therapeutic agents.

Single versus double occupancy solid lipid nanoparticles for delivery of the dual-acting bacteriocin, lacticin 3147.

The bacteriocin lacticin 3147 (lacticin) has shown activity against clinically relevant and antimicrobial-resistant bacteria such as Listeria monocytogenes and Clostridioides difficile. It is composed of two peptides, Ltnα and Ltnβ, which work together to form pores in the membrane of Gram-positive bacteria. Lacticin possesses poor aqueous solubility and is degraded by intestinal proteases.

An ion-paired moxifloxacin nanosuspension eye drop provides improved prevention and treatment of ocular infection.

There are numerous barriers to achieving effective intraocular drug administration, including the mucus layer protecting the ocular surface. For this reason, antibiotic eye drops must be used multiple times per day to prevent and treat ocular infections. Frequent eye drop use is inconvenient for patients, and lack of adherence to prescribed dosing regimens limits treatment efficacy and contributes to antibiotic resistance.

Docusate-Based Ionic Liquids of Anthelmintic Benzimidazoles Show Improved Pharmaceutical Processability, Lipid Solubility, and Activity against .

As the existing therapeutic modalities for the treatment of cryptococcal meningitis (CM) have suboptimal efficacy, repurposing existing drugs for the treatment of CM is of great interest. The FDA-approved anthelmintic benzimidazoles, albendazole, mebendazole, and flubendazole, have demonstrated potent but variable activity against , the predominant fungal species responsible for CM. We performed molecular docking studies to ascertain the interaction of albendazole, mebendazole, and flubendazole with a β-tubulin structure, which revealed differential binding interactions and explained the different efficacies reported previously and observed in this investigation.

Microemulsion-based gel for the transdermal delivery of rasagiline mesylate: In vitro and in vivo assessment for Parkinson's therapy.

Rasagiline mesylate (RSM) is a selective and irreversible monoamine oxidase B inhibitor used for the treatment of Parkinson's disease (PD). However, its unfavorable biopharmaceutical properties, such as extensive degradation in the gastrointestinal tract and first-pass metabolism are responsible for its low oral bioavailability and suboptimal therapeutic efficacy. Here, we report the feasibility of delivering RSM via the transdermal route using RSM containing microemulsion-based gel (RSM-MEG) to achieve effective management of PD.

Pharmaceutical design of a delivery system for the bacteriocin lacticin 3147.

Lacticin 3147 is a dual-acting two-peptide bacteriocin which is generally active against Gram-positive bacteria, including Listeria monocytogenes and antimicrobial-resistant bacteria such as Closteroides difficile in the colon. L. monocytogenes infections can cause life-long effects in the elderly and vulnerable and can cause severe complications in pregnant women.

The Importance of Apparent pKa in the Development of Nanoparticles Encapsulating siRNA and mRNA.

Polymer and lipid nanoparticles have been extensively used as carriers to address the biological barriers encountered in siRNA and mRNA delivery. We summarize the crucial role of nanoparticle charge and ionizability in complexing RNAs, binding to biological components, escaping from the endosome, and releasing RNAs into the cytoplasm. We highlight the significant impact of the apparent pKa of nanoparticles on their efficacy and toxicity, and the importance of optimizing pKa in the development of lead formulations for RNAs.

Synthesis and Characterization of Lipophilic Salts of Metformin to Improve Its Repurposing for Cancer Therapy.

Epidemiological evidence has accentuated the repurposing of metformin hydrochloride for cancer treatment. However, the extreme hydrophilicity and poor permeability of metformin hydrochloride are responsible for its poor anticancer activity and . Here, we report the synthesis and characterization of several lipophilic metformin salts containing bulky anionic permeation enhancers such as caprate, laurate, oleate, cholate, and docusate as counterions.

Pharmaceutically Acceptable Carboxylic Acid-Terminated Polymers Show Activity and Selectivity against HSV-1 and HSV-2 and Synergy with Antiviral Drugs.

Polyanionic macromolecules including carboxylate-terminated polymers (polycarboxylates) are capable of inhibiting sexually transmitted viruses such as human immunodeficiency virus (HIV) and herpes simplex virus (HSV). Cellulose acetate phthalate (CAP), a pharmaceutically acceptable pH-sensitive polycarboxylate polymer, showed promising prophylactic activity against HIV and HSV, but the instability of CAP in an aqueous environment prevented its clinical development. Interestingly, several pharmaceutically acceptable polycarboxylates have features similar to CAP with an aqueous stability significantly higher than that of CAP.

Co-delivery of IKBKE siRNA and cabazitaxel by hybrid nanocomplex inhibits invasiveness and growth of triple-negative breast cancer.

is an oncogene in triple-negative breast cancer (TNBC), and we demonstrate that IKBKE small interfering RNA (siRNA) inhibits the proliferation, migration, and invasion of TNBC cells. Despite the recent success of siRNA therapeutics targeting to the liver, there still remains a great challenge to deliver siRNAs to solid tumors. Here, we report a hybrid nanocomplex to co-deliver the IKBKE siRNA and cabazitaxel to TNBC to achieve an optimal antitumor effect.

Celiac Disease in a 16-Month-Old Child Presenting as Motor Regression.

Neurodevelopmental symptoms were previously believed to be a complication of celiac disease (CD) and rarely seen as presenting symptoms. One case has been reported so far where motor regression was the presenting symptom. We present a 16-month-old girl with postprandial vomiting and regression of motor skills.

Multi-Layered Nanomicelles as Self-Assembled Nanocarrier Systems for Ocular Peptide Delivery.

Despite the great potential of peptides as therapeutics, there is an unmet challenge in sustaining delivery of sufficient amounts in their native forms. This manuscript describes a novel nanocarrier capable of delivering functional small peptides in its native form. Self-assembling multi-layered nanomicelles composed of two polymers, polyoxyethylene hydrogenated castor oil 40 (HCO-40) and octoxynol 40 (OC-40), were designed to combine hydrophilic interaction and solvent-induced encapsulation of peptides and proteins.

Solid lipid nanoparticles of amphotericin B (AmbiOnp): in vitro and in vivo assessment towards safe and effective oral treatment module.

Amphotericin B, a gold standard broad spectrum antibiotic used in treatment of systemic fungal infections and visceral leishmaniasis, though is effective parenterally offers severe nephrotoxicity whereas the oral delivery is reported to give very meager oral bioavailability. Thus, to alleviate the toxicity and to improve oral bioavailability, an effective oral delivery approach in the form of solid lipid nanoparticles of amphotericin B (AmbiOnp) was reported earlier by our group. In this investigation, we report the predominant formation of nontoxic superaggregated form of amphotericin B, resulting from the probe sonication-assisted nanoprecipitation technique.

Colloidal soft nanocarrier for transdermal delivery of dopamine agonist: ex vivo and in vivo evaluation.

Ropinirole, an antiparkinsoism dopamine agonist, is used to treat Restless Legs Syndrome. However, orally it undergoes degradation in gastrointestinal tract and extensive first pass metabolism, resulting in its poor and variable bioavailability of the commercially available oral tablets. In the present investigation, soft nanocarriers, viz.

The influence of salinity and copper exposure on copper accumulation and physiological impairment in the sea anemone, Exaiptasia pallida.

Copper is a common pollutant in many aquatic environments, particularly those surrounding densely populated areas with substantial anthropogenic inputs. These same areas may also experience changes in salinity due to freshwater discharge and tidal influence. Biota that inhabit near-shore coastal environments may be susceptible to both stressors.

Controlled iontophoretic delivery of pramipexole: electrotransport kinetics in vitro and in vivo.

The objective of the study was to investigate the anodal iontophoretic delivery of pramipexole (PRAM), a dopamine agonist used for the treatment of Parkinson's disease, in order to determine whether therapeutic amounts of the drug could be delivered across the skin. Preliminary iontophoretic experiments were performed in vitro using porcine ear and human abdominal skin. These were followed by a pharmacokinetic study in male Wistar rats to determine the drug input rate in vivo.