Linh Dinh

Background: Hydrogels are 3D networks of hydrophilic polymers with various biomedical applications, including tissue regeneration, wound healing, and localized drug delivery. Hydrogel conjugation links therapeutic agents to a hydrogel network, creating a delivery system with adjustable and flexible hydrogel properties and drug activity, allowing for controlled release and enhanced drug stability. Conjugating therapeutic agents to hydrogels provides innovative delivery formats, including injectable and sprayable dosage forms, which facilitate localized and long-lasting delivery. This approach enables non-viral therapeutic methods, such as insertional mutagenesis, and minimally invasive drug administration. Scope and Objectives: While numerous reviews have analyzed advancements in hydrogel synthesis, characterization, properties, and hydrogels as a drug delivery vehicle, this review focuses on hydrogel conjugation, which enables the precise functionalization of hydrogels with small molecules and macromolecules. Subsequently, a description and discussion of several bio-conjugated hydrogel systems, as well as binding motifs (e.g., “click” chemistry, functional group coupling, enzymatic ligation, etc.) and their potential for clinical translation, are provided. In addition, the integration of therapeutic agents with nucleic acid-based hydrogels can be leveraged for sequence-specific binding, representing a leap forward in biomaterials. Key findings: Special attention was given to the latest conjugation approaches and binding motifs that are useful for designing hydrogel-based drug delivery systems. The review systematically categorizes hydrogel conjugates for drug delivery, focusing on conjugating hydrogels with major classes of therapeutic agents, including small-molecule drugs, nucleic acids, proteins, etc., each with distinct conjugation challenges. The design principles were discussed along with their properties and drug release profiles. Finally, future opportunities and current limitations of conjugated hydrogel systems are addressed.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, remains a major global health threat. The virus enters host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Several small-molecule antiviral drugs, including molnupiravir, favipiravir, remdesivir, and nirmatrelvir have been shown to inhibit SARS-CoV-2 replication and are approved for treating SARS-CoV-2 infections. Nirmatrelvir inhibits the viral main protease (M^pro), a key enzyme for processing polyproteins in viral replication. In contrast, molnupiravir, favipiravir, and remdesivir are prodrugs that target RNA-dependent RNA polymerase (RdRp), which is crucial for genome replication and subgenomic RNA production. However, undergoing extensive metabolism profoundly impacts their therapeutic effects. Carboxylesterases (CES) are a family of enzymes that play an essential role in the metabolism of many drugs, especially prodrugs that require activation through hydrolysis. Molnupiravir is activated by carboxylesterase-2 (CES2), while remdesivir is hydrolytically activated by CES1 but inhibits CES2. Nirmatrelvir and remdesivir are oxidized by the same cytochrome P450 (CYP) enzyme. Additionally, various transporters are involved in the uptake or efflux of these drugs and/or their metabolites. It is well established that drug-metabolizing enzymes and transporters are differentially expressed depending on the cell type, and these genes exhibit significant polymorphisms. In this review, we examine how CES-related cellular and genetic factors influence the therapeutic activities of these widely used COVID-19 medications. This article highlights implications for improving product design, targeted inhibition, and personalized medicine by exploring genetic variations and their impact on drug metabolism and efficacy.

Celecoxib (CEL), a nonsteroidal anti-inflammation drug (NSAID), is categorized as a Class II drug (low solubility, high permeability) in the Biopharmaceutics Classification System (BCS). The aim of this study is to develop a novel formulation of CEL nanosuspensions in the form of dried powder for tableting or capsuling. In this study, CEL was formulated into nanosuspensions to improve its solubility. CEL nanosuspensions were prepared using the precipitation method followed by high-pressure homogenization. Drying of the nanosuspensions was performed by spray drying and freeze drying. We examined the impact of various formulation and processing parameters on the nanoparticles. The CEL nanoparticles were characterized by particle size analysis, differential scanning calorimetry (DSC), powder X-Ray diffraction (PXRD), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), and dissolution tests. The choice of solvent, stabilizer, and surfactant appeared to have significant impacts on the crystallization and particle size and, consequently, the solubility of the CEL nanoparticles. CEL chemical stability was maintained throughout both drying processes. Both spray-dried and freeze-dried CEL nanosuspensions showed rapid dissolution profiles compared to raw CEL due to the nanosized particle dispersion with the presence of a lag phase. The freeze-dried nanosuspension showed a slight delay in the first 20 min compared to the spray-dried nanosuspension, after which dissolution progressed with a lag phase that represents aggregation.

Nano-encapsulation and conjugation are the main strategies employed for drug delivery. Nanoparticles help improve encapsulation and targeting efficiency, thus optimizing therapeutic efficacy. Through nanoparticle technology, replacement of a defective gene or delivery of a new gene into a patient’s genome has become possible. Lipid nanoparticles (LNPs) loaded with genetic materials are designed to be delivered to specific target sites to enable gene therapy. The lipid shells protect the fragile genetic materials from degradation, then successfully release the payload inside of the cells, where it can integrate into the patient’s genome and subsequently express the protein of interest. This review focuses on the development of LNPs and nano-pharmaceutical techniques for improving the potency of gene therapies, reducing toxicities, targeting specific cells, and releasing genetic materials to achieve therapeutic effects. In addition, we discuss preparation techniques, encapsulation efficiency, and the effects of conjugation on the efficacy of LNPs in delivering nucleic acid materials.

Lyotropic liquid crystals (LLCs) are liquids that have crystalline structures. LLCs as drug delivery systems that can deliver hydrophobic, hydrophilic, and amphiphilic agents. Due to their unique phases and structures, LLCs can protect both small molecules and biologics from the gastrointestinal tract’s harsh environment, thus making LLCs attractive as carriers for oral drug delivery. In this review, we discuss the advantages of LLCs and LLCs as oral formulations targeting intestinal lymphatic transport. In oral LLC formulations, the relationship between the micelle compositions and the resulting LLC structures as well as intestinal transport and absorption were determined. In addition, we further demonstrated approaches for the enhancement of intestinal lymphatic transport: (1) lipid-based LLCs promoting chylomicron secretion and (2) the design of LLC nanoparticles with M cell-triggered ligands for targeting the M cell pathway. In this review, we introduce LLC drug delivery systems and their characteristics. Our review focuses on recent approaches using oral LLC drug delivery strategies targeting the intestinal lymphatic system to enhance drug bioavailability.