Hydrogels are an important class of biomaterials with the unique property of high‐water content in a crosslinked polymer network. In particular, chemically crosslinked hydrogels have made a great clinical impact in past years because of their desirable mechanical properties and tunability of structural and chemical properties. Various polymers and step‐growth crosslinking chemistries are harnessed for fabricating such covalently crosslinked hydrogels for translational research. However, selecting appropriate crosslinking chemistries and polymers for the intended clinical application is time‐consuming and challenging. It requires the integration of polymer chemistry knowledge with thoughtful crosslinking reaction design. This task becomes even more challenging when other factors such as the biological mechanisms of the pathology, practical administration routes, and regulatory requirements add additional constraints. In this review, key features of crosslinking chemistries and polymers commonly used for preparing translatable hydrogels are outlined and their performance in biological systems is summarized. The examples of effective polymer/crosslinking chemistry combinations that have yielded clinically approved hydrogel products are specifically highlighted. These hydrogel design parameters in the context of the regulatory process and clinical translation barriers, providing a guideline for the rational selection of polymer/crosslinking chemistry combinations to construct hydrogels with high translational potential are further considered.

Monoclonal antibodies (mAbs) are currently used for the treatment of numerous conditions including cancer, psoriasis, arthritis, and atopic dermatitis, among others. All mAbs are currently administered by either intravenous or subcutaneous injections. Herein, the use of a novel ionic liquid and deep eutectic solvent, choline and glycolate (CGLY), as a platform for gastrointestinal administration of therapeutic antibodies is reported. CGLY maintains the stability and structure of TNFα antibody. CGLY significantly enhances paracellular transport of TNFα antibody in vitro. CGLY also reduces the viscosity of the intestinal mucus, another key barrier for antibody transport. In vivo results in rats demonstrate that CGLY effectively delivers TNFα antibody into the intestinal mucosa as well as systemic circulation. One week repeat dose study followed by histology and serum biochemistry analysis indicates that CGLY is well tolerated by rats. Overall, this work illustrates the promise of using choline-based ionic liquids and deep eutectic solvents as an oral delivery platform for local as well as systemic delivery of therapeutic antibodies.

Colorectal cancer, common in both men and women, occurs when tumors form in the linings of the colon. Common treatments of colorectal cancer include surgery, chemotherapy, and radiation therapy; however, many colorectal cancer treatments often damage healthy tissues and cells, inducing severe side effects. Conventional chemotherapeutic agents such as doxorubicin (Dox) can be potentially used for the treatment of colorectal cancer; however, they suffer from limited targeting and lack of selectivity. Here, we report that doxorubicin complexed to hyaluronic acid (HA) (HA-Dox) exhibits an unusual behavior of high accumulation in the intestines for at least 24 hr when injected intravenously. Intravenous administrations of HA-Dox effectively preserved the mucosal epithelial intestinal integrity in a chemical induced colon cancer model in mice. Moreover, treatment with HA-Dox decreased the expression of intestinal apoptotic and inflammatory markers. The results suggest that HA-Dox could effectively inhibit the development of colorectal cancer in a safe manner, which potentially be used a promising therapeutic option.

Skin cancer is one of the most common types of cancer in the United States and worldwide. Topical products are effective for treating cancerous skin lesions when surgery is not feasible. However, current topical products induce severe irritation, light-sensitivity, burning, scaling, and inflammation. Using hyaluronic acid (HA), we engineered clinically translatable polymer-drug conjugates of doxorubicin and camptothecin termed, DOxorubicin and Camptothecin Tailored at Optimal Ratios (DOCTOR) for topical treatment of skin cancers. When compared to the clinical standard, Efudex, DOCTOR exhibited high cancer-cell killing specificity with superior safety to healthy skin cells. In vivo studies confirmed its efficacy in treating cancerous lesions without irritation or systemic absorption. When tested on patient-derived primary cells and live-skin explants, DOCTOR killed the cancer with a selectivity as high as 21-fold over healthy skin tissue from the same donor. Collectively, DOCTOR provides a safe and potent option for treating skin cancer in the clinic.

Cancer therapy is increasingly shifting toward targeting the tumor immune microenvironment and influencing populations of tumor infiltrating lymphocytes. Breast cancer presents a unique challenge as tumors of the triple-negative breast cancer subtype employ a multitude of immunosilencing mechanisms that promote immune evasion and rapid growth. Treatment of breast cancer with chemotherapeutics has been shown to induce underlying immunostimulatory responses that can be further amplified with the addition of immune-modulating agents. Here, we investigate the effects of combining doxorubicin (DOX) and gemcitabine (GEM), two commonly used chemotherapeutics, with monophosphoryl lipid A (MPLA), a clinically used TLR4 adjuvant derived from liposaccharides. MPLA was incorporated into the lipid bilayer of liposomes loaded with a 1:1 molar ratio of DOX and GEM to create an intravenously administered treatment. In vivo studies indicated excellent efficacy of both GEM-DOX liposomes and GEM-DOX-MPLA liposomes against 4T1 tumors. In vitro and in vivo results showed increased dendritic cell expression of CD86 in the presence of liposomes containing chemotherapeutics and MPLA. Despite this, a tumor rechallenge study indicated little effect on tumor growth upon rechallenge, indicating the lack of a long-term immune response. GEM/DOX/MPLA-L displayed remarkable control of the primary tumor growth and can be further explored for the treatment of triple-negative breast cancer with other forms of immunotherapy.

The mucus barrier lining the gastrointestinal tract poses a significant barrier to the oral delivery of macromolecular drugs. Successful approaches to overcoming this barrier have primarily focused on reducing drug and carrier interactions with mucus or disrupting the mucus layer directly. Choline‐based ionic liquids (ILs) such as choline geranate and choline glycolate (CGLY) have recently been shown to be effective in enhancing the intestinal absorption of macromolecules such as insulin and immunoglobulin (IgG), respectively. Herein, the use of choline‐based ILs as mucus‐modulating agents for safely improving drug penetration through mucus is described. Choline‐based ILs significantly increase the diffusion rates of cationic dextrans through mucin solution. Choline‐maleic acid (CMLC 2:1) enhances the diffusion of 4 kDa cationic dextran in mucin solution by more than fourfold when compared to phosphate‐buffered saline control. Choline‐based ILs also reduce mucus viscosity without significantly impacting the native mucus gel structure. In vitro studies in a mucus‐secreting coculture model with Caco‐2 and HT29MTX‐E12 cells further demonstrate the effectiveness of ILs in improving transport of cationic molecules in the presence of secreted mucus. This work demonstrates the potential for choline‐based ionic liquids to be used as nondestructive mucus‐modulating agents for enabling enhanced oral delivery of macromolecular drugs.

Ionic liquids (ILs) possess unique solvation and biological properties for drug delivery. Choline and geranic acid (CAGE) in particular, has been successfully formulated to orally deliver insulin and hydrophobic therapeutics such as sorafenib (SRF). However, relatively little is known about the effect of CAGE on intracellular delivery of drugs. Here the effect of low‐concentration CAGE (<2 mg mL−1) on the delivery of SRF into cancer cells (4T1, PANC‐1, and HT29) as well as intestine epithelium cells (Caco‐2) is studied. The anti‐cancer effect of SRF is enhanced by up to fivefold in the presence of CAGE (0.5 mg mL−1). The effect is mediated not by enhancing the cellular uptake of SRF but by improving intracellular SRF retention by inhibiting exocytosis. Moreover, CAGE improves the anti‐tumor effect of SRF by increasing apoptosis and blocking cell‐cycle progression. Moreover, CAGE significantly enhances the penetration of SRF into and across multicellular constructs with multiple mechanisms involved. Collectively, the administration of ILs such as CAGE combined with SRF may offer a novel therapy to better inhibit tumor progression.

Oral delivery of biologic drugs is a highly desired yet challenging goal because of the many barriers posed by the GI tract. Ionic liquids (ILs) and deep eutectic solvents (DESs) such as choline and geranate (CAGE) have demonstrated the potential to improve intestinal absorption of insulin and poorly soluble drugs. As with other delivery agents, localization of the ILs in the intestine can enhance the delivery potential by increasing local concentrations while maintaining low off-target concentrations, thus improving the therapeutic window of the ILs. Here, we describe a method of encapsulating CAGE into a gel using PVA, forming a mucoadhesive ionogel patch (CAGE-patch) designed to adhere to the intestine. CAGE-patches formed via repeated freeze−thaw cycles demonstrated mucoadhesive strength, swelling, and controlled release of both CAGE and insulin. In vitro transport studies revealed a more than 30% increase in insulin transport when compared to controls across Caco-2 and HT29-MTX-E12 coculture layers. This design provides a novel approach to localize ionic liquids and therapeutics in the GI tract for enhanced oral delivery.