Degradable Hydrogel for Sustained Localized Delivery of Anti-Tumor Drugs.

Disadvantages of systemically administered immunomodulatory anti-tumor therapies include poor efficacy and high toxicity. Direct intratumoral injection of a drug is often associated with rapid efflux from the site of administration, thus reducing local exposure and therapeutic efficacy, while potentially increasing systemic adverse events. To address this, a sustained release prodrug technology was developed using a transient conjugation (TransCon) technology to provide long-term high local drug exposure after injection in the tumor while minimizing systemic exposure.

Intratumoral delivery of TransCon TLR7/8 Agonist promotes sustained anti-tumor activity and local immune cell activation while minimizing systemic cytokine induction.

Background: Intratumoral (IT) delivery of toll-like receptor (TLR) agonists has shown encouraging anti-tumor benefit in preclinical and early clinical studies. However, IT delivery of TLR agonists may lead to rapid effusion from the tumor microenvironment (TME), potentially limiting the duration of local inflammation and increasing the risk of systemic adverse events.

Methods: To address these limitations, TransCon TLR7/8 Agonist-an investigational sustained-release prodrug of resiquimod that uses a TransCon linker and hydrogel technology to achieve sustained and predictable IT release of resiquimod-was developed.

Peptidotriazolamers Inhibit Aβ(1-42) Oligomerization and Cross a Blood-Brain-Barrier Model.

In peptidotriazolamers every second peptide bond is replaced by a 1H-1,2,3-triazole. Such foldamers are expected to bridge the gap in molecular weight between small-molecule drugs and protein-based drugs. Amyloid β (Aβ) aggregates play an important role in Alzheimer's disease.

1,4-Disubstituted 1-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties.

Peptidotriazolamers are hybrid foldamers with features of peptides and triazolamers, containing alternation of amide bonds and 1,4-disubstituted 1-1,2,3-triazoles with conservation of the amino acid side chains. We report on the synthesis of a new class of peptidomimetics, containing 1,4-disubstituted 1-1,2,3-triazoles in alternation with amide bonds and the elucidation of their conformational properties in solution. Based on enantiomerically pure propargylamines bearing the stereogenic center in the propargylic position and α-azido esters, building blocks were obtained by copper-catalyzed azide-alkyne cycloaddition.

1,5-Disubstituted 1,2,3-Triazole-Containing Peptidotriazolamers: Design Principles for a Class of Versatile Peptidomimetics.

Peptidotriazolamers are hybrid foldamers combining features of peptides and triazolamers-repetitive peptidomimetic structures with triazoles replacing peptide bonds. We report on the synthesis of a new class of peptidomimetics, containing 1,5-disubstituted 1,2,3-triazoles in an alternating fashion with amide bonds and the analysis of their conformation in solid state and solution. Homo- or heterochiral peptidotriazolamers were obtained from enantiomerically pure propargylamines with stereogenic centers in the propargylic position and α-azido esters by ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) under microwave conditions in high yields.

Amber-Compatible Parametrization Procedure for Peptide-like Compounds: Application to 1,4- and 1,5-Substituted Triazole-Based Peptidomimetics.

Peptidomimetics are molecules of particular interest in the context of drug design and development. They are proteolytically and metabolically more stable than their natural peptide counterparts but still offer high specificity toward their biological targets. In recent years, 1,4- and 1,5-disubstituted 1,2,3-triazole-based peptidomimetics have emerged as promising lead compounds for the design of various inhibitory and tumor-targeting molecules as well as for the synthesis of peptide analogues.