A Pseudo-Surfactant Chemical Permeation Enhancer to Treat Otitis Media via Sustained Transtympanic Delivery of Antibiotics.

Chemical permeation enhancers (CPEs) represent a prevalent and safe strategy to enable noninvasive drug delivery across skin-like biological barriers such as the tympanic membrane (TM). While most existing CPEs interact strongly with the lipid bilayers in the stratum corneum to create defects as diffusion paths, their interactions with the delivery system, such as polymers forming a hydrogel, can compromise gelation, formulation stability, and drug diffusion. To overcome this challenge, differing interactions between CPEs and the hydrogel system are explored, especially those with sodium dodecyl sulfate (SDS), an ionic surfactant and a common CPE, and those with methyl laurate (ML), a nonionic counterpart with a similar length alkyl chain. Notably, the use of ML effectively decouples permeation enhancement from gelation, enabling sustained delivery across TMs to treat acute otitis media (AOM), which is not possible with the use of SDS. Ciprofloxacin and ML are shown to form a pseudo-surfactant that significantly boosts transtympanic permeation. The middle ear ciprofloxacin concentration is increased by 70-fold in vivo in a chinchilla AOM model, yielding superior efficacy and biocompatibility than the previous highest-performing formulation. Beyond improved efficacy and biocompatibility, this single-CPE formulation significantly accelerates its progression toward clinical deployment.

Inner Ear Drug Delivery for Sensorineural Hearing Loss: Current Challenges and Opportunities.

Most therapies for treating sensorineural hearing loss are challenged by the delivery across multiple tissue barriers to the hard-to-access anatomical location of the inner ear. In this review, we will provide a recent update on various pharmacotherapy, gene therapy, and cell therapy approaches used in clinical and preclinical studies for the treatment of sensorineural hearing loss and approaches taken to overcome the drug delivery barriers in the ear. Small-molecule drugs for pharmacotherapy can be delivered via systemic or local delivery, where the blood-labyrinth barrier hinders the former and tissue barriers including the tympanic membrane, the round window membrane, and/or the oval window hinder the latter. Meanwhile, gene and cell therapies often require targeted delivery to the cochlea, which is currently achieved via intra-cochlear or intra-labyrinthine injection. To improve the stability of the biomacromolecules during treatment, e.g., RNAs, DNAs, proteins, additional packing vehicles are often required. To address the diverse range of biological barriers involved in inner ear drug delivery, each class of therapy and the intended therapeutic cargoes will be discussed in this review, in the context of delivery routes commonly used, delivery vehicles if required (e.g., viral and non-viral nanocarriers), and other strategies to improve drug permeation and sustained release (e.g., hydrogel, nanocarriers, permeation enhancers, and microfluidic systems). Overall, this review aims to capture the important advancements and key steps in the development of inner ear therapies and delivery strategies over the past two decades for the treatment and prophylaxis of sensorineural hearing loss.

On-Demand Synthesis of Antiseptics at the Site of Infection for Treatment of Otitis Media.

Otitis media (OM) is the main reason for pediatric antibiotic prescriptions. The current treatment mandates a rigorous regimen of multidose antibiotics over 5-10 days. The systemic antibiotic exposure and often prematurely terminated treatment due to the challenge of drug administration to young patients are believed to breed antibiotic resistance. To address these challenges, we designed a local treatment that converted a metabolic product (H2O2) of an OM pathogen (Streptococcus pneumoniae) into a potent antiseptic (HOBr), a reaction catalyzed by locally administered vanadium pentoxide nanowires. The therapeutic, HOBr, was only synthesized in the presence of the pathogen, enabling on-demand generation of therapeutics for OM treatment. Hypohalous acids are broad-spectrum and have a long history in general disinfection applications without breeding substantial drug resistance. A single dose of the nanowire formulation eradicated OM in a standard chinchilla model in 7 days with no observable tissue toxicity or negative impact on hearing sensitivity.

A therapeutic convection-enhanced macroencapsulation device for enhancing ß cell viability and insulin secretion.

Islet transplantation for type 1 diabetes treatment has been limited by the need for lifelong immunosuppression regimens. This challenge has prompted the development of macroencapsulation devices (MEDs) to immunoprotect the transplanted islets. While promising, conventional MEDs are faced with insufficient transport of oxygen, glucose, and insulin because of the reliance on passive diffusion. Hence, these devices are constrained to two-dimensional, wafer-like geometries with limited loading capacity to maintain cells within a distance of passive diffusion. We hypothesized that convective nutrient transport could extend the loading capacity while also promoting cell viability, rapid glucose equilibration, and the physiological levels of insulin secretion. Here, we showed that convective transport improves nutrient delivery throughout the device and affords a three-dimensional capsule geometry that encapsulates 9.7-fold-more cells than conventional MEDs. Transplantation of a convection-enhanced MED (ceMED) containing insulin-secreting ß cells into immunocompetent, hyperglycemic rats demonstrated a rapid, vascular-independent, and glucose-stimulated insulin response, resulting in early amelioration of hyperglycemia, improved glucose tolerance, and reduced fibrosis. Finally, to address potential translational barriers, we outlined future steps necessary to optimize the ceMED design for long-term efficacy and clinical utility.

A 3D culture platform enables development of zinc-binding prodrugs for targeted proliferation of ß cells.

Advances in treating ß cell loss include islet replacement therapies or increasing cell proliferation rate in type 1 and type 2 diabetes, respectively. We propose developing multiple proliferation-inducing prodrugs that target high concentration of zinc ions in ß cells. Unfortunately, typical two-dimensional (2D) cell cultures do not mimic in vivo conditions, displaying a markedly lowered zinc content, while 3D culture systems are laborious and expensive. Therefore, we developed the Disque Platform (DP)-a high-fidelity culture system where stem cell-derived ß cells are reaggregated into thin, 3D discs within 2D 96-well plates. We validated the DP against standard 2D and 3D cultures and interrogated our zinc-activated prodrugs, which release their cargo upon zinc chelation-so preferentially in ß cells. Through developing a reliable screening platform that bridges the advantages of 2D and 3D culture systems, we identified an effective hit that exhibits 2.4-fold increase in ß cell proliferation compared to harmine.