Long-acting acid-sensitive ketal-linked dexamethasone microcrystals for treating experimental autoimmune uveitis.

Corticosteroids have for some time been used as first-line drugs for the topical treatment of noninfectious uveitis, but poor ocular bioavailability and the rapid clearance of eye drops necessitate frequent dosing, reducing patient compliance. In this study, we used an acid-sensitive stearoxyl-ketal-dexamethasone pro-drug microcrystals (SKD MCs), which is consistently safe and effective in the control of uveitis inflammation in rats. We used a rat model of experimental autoimmune uveitis (EAU) to evaluate the effects of SKD MCs in terms of clinical manifestations, molecular biology, pathological histology, and visual electrophysiology compared to dexamethasone sodium phosphate injection or phosphate-buffered saline.

Microcrystals of Ketal-Linked Paliperidone Prodrugs for Long-Acting Antipsychotics.

Intramuscularly injectable long-acting prodrug-based microcrystals (MCs) are of particular interest for chronic disease management. Nevertheless, current prevalently used linkers degraded by enzymes have the potential drawback of substantial differences in enzyme levels between individuals. Here, we reported the synthesis of a stearyl-modified paliperidone prodrug (SKP) with an acid-sensitive ketal linker for developing long-acting MC antipsychotics.

Carrier strategies boost the application of CRISPR/Cas system in gene therapy.

Emerging clustered regularly interspaced short palindromic repeat/associated protein (CRISPR/Cas) genome editing technology shows great potential in gene therapy. However, proteins and nucleic acids suffer from enzymatic degradation in the physiological environment and low permeability into cells. Exploiting carriers to protect the CRISPR system from degradation, enhance its targeting of specific tissues and cells, and reduce its immunogenicity is essential to stimulate its clinical applications.

Modular ketal-linked prodrugs and biomaterials enabled by organocatalytic transisopropenylation of alcohols.

Isopropenyl ethers are critical intermediates for accessing medicinally valuable ketal-based prodrugs and biomaterials, but traditional approaches for the synthesis of isopropenyl ethers suffer from poor functional group compatibility and harsh reaction conditions. Here, we develop an organocatalytic transisopropenylation approach to solve these challenges, enabling the synthesis of isopropenyl ethers from various hydroxyl-group-containing small-molecule drugs, polymers, and functional building blocks. The method provides a straightforward and versatile synthesis of isopropenyl ethers, features excellent tolerance of diverse functional groups, applies to a wide range of substrates, and allows scalable synthesis.

Intra-Articular injection of acid-sensitive stearoxyl-ketal-dexamethasone microcrystals for long-acting arthritis therapy.

Despite advances in treatment of chronic arthritis, there is still a strong need for the development of long-acting formulations that can enable local and sustained drug release at the inflamed tissues. In this work, we fabricated microcrystals of an acid-sensitive stearoxyl-ketal-dexamethasone prodrug for treatment of arthritis. Microcrystals of the prodrug with two sizes were successfully engineered and showed pH-dependent hydrolysis kinetics .

Acid-sensitive PEGylated paclitaxel prodrug nanoparticles for cancer therapy: Effect of PEG length on antitumor efficacy.

Paclitaxel is one of the most widely used anticancer agents, but strong side effects and low bioavailability limit its clinical efficacy. The use of tumor microenvironment-responsive prodrugs is promising to solve these problems, and a smart linkage is crucial to achieve the efficient release of paclitaxel from such prodrugs in tumor. Herein, an acid-responsive acetone-based acyclic ketal linkage is used to construct paclitaxel prodrugs with different length of poly(ethylene glycol) (PEG).

Modular Acid-Activatable Acetone-Based Ketal-Linked Nanomedicine by Dexamethasone Prodrugs for Enhanced Anti-Rheumatoid Arthritis with Low Side Effects.

Given the physically encapsulated payloads with drug burst release and/or low drug loading, it is critical to initiate an innovative prodrug strategy to optimize the design of modular nanomedicines. Here, we designed modular pH-sensitive cetone-based etal-linked rodrugs of amethasone (AKP-dexs) and formulated them as nanoparticles. We comprehensively studied the relationships between AKP-dex structure and properties, and we selected two types of AKP-dex-loaded nanoparticles for in vivo studies on the basis of their size, drug loading, and colloidal stability.

Synthesis of Poly(acyclic orthoester)s: Acid-Sensitive Biomaterials for Enhancing Immune Responses of Protein Vaccine.

While poly(acyclic orthoester)s (PAOEs) have many appealing features for drug delivery, their application is significantly hindered by a lack of facile synthetic methods. Reported here is a simple method for synthesizing acyclic diketene acetal monomers from diols and vinyl ether, and their polymerization with a diol to first synthesize PAOEs. The PAOEs rapidly hydrolyze at lysosomal pH.

Acid-Triggered Release of Native Gemcitabine Conjugated in Polyketal Nanoparticles for Enhanced Anticancer Therapy.

Nucleoside analogue drugs are widely used in cancer therapy and antiviral therapy, while fast metabolism, drug resistance, and severe side effects significantly limit their clinical applications. To address these issues, a variety of ester- and amide-linked prodrugs and their nanoparticulate formulations have been devised. However, most of these prodrugs suffer from inefficient transformation to native drugs in tumor.

A comparative study on agarose acetate and PDLLA scaffold for rabbit femur defect regeneration.

The development of degradable polymer scaffolds is a key issue in bone regeneration. Poly(D, L-lactide) (PDLLA) and its derivatives have usually been applied to the construction of degradable scaffolds, but these scaffolds had problems with acidic degradation products and quick loss of mechanic strength during the later degradation, which usually led to scaffold collapse and cavity formation because of the slower rate of bone regeneration. In the present paper, a polysaccharide derivative, agarose acetate (AGA), was synthesized and a novel porous AGA scaffold was successfully developed through a salt-leaching process.

LED 209 conjugated chitosan as a selective antimicrobial and potential anti-adhesion material.

The rapid emergence of antibiotic-resistant Gram-negative bacteria (GNB) is becoming a global healthcare concern, and it urgently needs novel strategies to match the clinical challenge. In this work, we conjugated chitosan (CS) with LED 209, a highly selective inhibitor of QseC of GNB, to create the novel selective antimicrobial agent CS/LED. The data of FT-IR, NMR and elemental analysis for CS/LED conjugates proved the successful conjugation of CS with LED 209.

Fabrication and biocompatibility of agarose acetate nanofibrous membrane by electrospinning.

In the present paper, agarose acetate (AGA) nanofibrous membranes containing different weight percentages of β-tricalcium phosphate (β-TCP) were successfully developed through electrospinning. The fibers in the nanofibrous membranes had a rough surface due to the β-TCP particles which were uniformly dispersed within or on the surface of AGA fibers. Rat-bone marrow-derived mesenchymal stem cells (rBMSCs) were cultured on the AGA based nanofibrous membranes while showed a good adhesion and proliferation.