Biology subjects

Agus, E.

Publications and source records attributed to Agus, E..

3 recordsLinked to original sources

bioRxiv2025

A Precisely Controlled Long-Acting Immunosuppression Platform Enables Prolonged Survival of Vascularized Composite Allografts

Vascularized composite allotransplantation (VCA) restores complex tissue defects but demands lifelong systemic immunosuppression. Oral tacrolimus (TAC) is limited by a narrow therapeutic window, pharmacokinetic variability, adherence challenges, and toxicity. Local delivery could mitigate these issues, yet clinical translation has been hindered by burst release, short duration, and the inability to co-deliver agents. We developed PRECISE (Programmable, REtrievable, Controlled ImmunoSuppression Encapsulator), an injectable, in-situ-forming PLGA depot that achieves long-acting, tightly controlled TAC release via structure-guided co-formulation with drug-binding agents (DBAs). GRAS small molecules (e.g., EGCG, maltotriose) identified by in silico docking and in vitro screening suppressed burst and modulated solvent efflux. Notably, rapamycin (RAPA) served dually as an mTOR inhibitor and a TAC-binding excipient, enabling synchronized dual-agent delivery. PRECISE eliminated burst in vitro and produced coordinated TAC+RAPA release with clinically compatible injectability. In rats, monthly intragraft dosing maintained systemic TAC/RAPA within the therapeutic window ([~]5-10 ng/mL) for >300 days, prolonged hindlimb allograft survival, expanded Tregs, and induced donor-specific hyporesponsiveness. Surgical retrieval of the depot triggered rapid TAC decline, demonstrating reversibility. In a stringent, fully MHC-mismatched porcine VCA model, PRECISE maintained on-target drug levels and extended graft survival beyond 90 days with minimal rejection and preserved vascular integrity. PRECISE is, to our knowledge, the first retrievable, injectable platform to deliver long-acting, dual-agent immunosuppression with controlled kinetics, rapid attainment of therapeutic steady state, and sustained graft protection. Its modular, structure-guided design enables clinical translation across VCA and solid-organ transplantation, delivering precise, durable, and safer immunosuppression.

bioengineering↗

bioRxiv2023

An injectable in situ crosslinkable platform for ultra-long-acting delivery of hydrophilic therapeutics

Achieving ultra-long-term release of hydrophilic drugs over several months remains a significant challenge for existing long-acting injectables (LAIs). Existing platforms, such as in situ forming implants (ISFI), exhibit high burst release due to solvent efflux and microsphere-based approaches lead to rapid drug diffusion due to significant water exchange and large pores. Addressing these challenges, we have developed an injectable platform that, for the first time, achieves ultra-long-term release of hydrophilic drugs for over six months. This system employs a methacrylated ultra-low molecular weight pre-polymer (polycaprolactone) to create in situ cross-linked depots (ISCD). The ISCDs solvent-free design and dense mesh network, both attributed to the ultra-low molecular weight of the pre-polymer, effectively minimizes burst release and water influx/efflux. In vivo studies in rats demonstrate that ISCD outperforms ISFI by achieving lower burst release and prolonged drug release. We demonstrated the versatility of ISCD by showcasing ultra-long-term delivery of several hydrophilic drugs, including antiretrovirals (tenofovir alafenamide, emtricitabine, abacavir, and lamivudine), antibiotics (vancomycin and amoxicillin) and an opioid antagonist naltrexone. Additionally, ISCD achieved ultra-long-term release of the hydrophobic drug tacrolimus and enabled co-delivery of hydrophilic drug combinations encapsulated in a single depot. We also identified design parameters to tailor the polymer network, tuning drug release kinetics and ISCD degradation. Pharmacokinetic modeling predicted over six months of drug release in humans, significantly surpassing the one-month standard achievable for hydrophilic drugs with existing LAIs. The platforms biodegradability, retrievability, and biocompatibility further underscore its potential for improving treatment adherence in chronic conditions.

bioengineering↗

bioRxiv2023

A Drug-Free Pathogen Capture and Neutralizing Nasal Spray to Prevent Emerging Respiratory Infections

Respiratory infections pose a global health crisis. Vaccines are pathogen specific, and new vaccines are needed for mutants and emerging pathogens. Here, we report a "drug free" prophylactic platform - a "Pathogen Capture and Neutralizing Spray" (PCANS) that acts via a multi-pronged approach to prevent a broad spectrum of respiratory infections. PCANS forms a protective coating in the nasal cavity that enhances the capture of large respiratory droplets. The coating acts as a physical barrier against a broad spectrum of viruses and bacteria, and rapidly neutralizes them, reducing the pathogen load by >99.99%. In mice, PCANS showed nasal retention for at least 8 h and was safe for daily administration. A single prophylactic dose of PCANS protected mice against supra-lethal dosages of a mouse-adapted H1N1 Influenza virus (PR8), reduced lung viral titer by >99.99%, improved survival, and suppressed pathological manifestations. Together, our data suggest PCANS as a promising daily-use prophylactic approach against current and emerging respiratory infections.

bioengineering↗