Pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) drugs are effective at preventing human immunodeficiency virus (HIV) transmission. However, implementation of PrEP presents significant challenges due to poor user adherence, low accessibility to ARVs and multiple routes of HIV exposure. To address these challenges, we developed the nanochannel delivery implant (NDI), a subcutaneously implantable device for sustained and constant delivery of tenofovir alafenamide (TAF) and emtricitabine (FTC) for HIV PrEP. Unlike existing drug delivery platforms with finite depots, the NDI incorporates ports allowing for transcutaneous refilling upon drug exhaustion. NDI-mediated drug delivery in rhesus macaques resulted in sustained release of both TAF and FTC for 83 days, as indicated by concentrations of TAF, FTC and their respectively metabolites in plasma, PBMCs, rectal mononuclear cells and tissues associated with HIV transmission. Notably, clinically relevant preventative levels of tenofovir diphosphate were achieved as early as 3 days after NDI implantation. We also demonstrated the feasibility of transcutaneous drug refilling to extend the duration of PrEP drug delivery in NHPs. Overall, the NDI represents an innovative strategy for long-term HIV PrEP administration in both developed and developing countries.

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Mounting evidence demonstrates that combining radiation therapy (RT) with immunotherapy can reduce tumor burden in a subset of patients. However, conventional systemic delivery of immunotherapeutics is often associated with significant adverse effects, which force treatment cessation. The aim of this study was to investigate a minimally invasive

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Tumor uptake and biodistribution of immunotherapy is associated with clinical response as well as toxicity. To augment immunotherapy bioavailability in the tumor, an intratumoral administration route via direct injection or local release technologies has emerged as an appealing approach. Here the biodistribution of an agonistic anti-CD40 monocolonal antibody (CD40 mAb) when sustainably delivered via an intratumoral nanofluidic drug-eluting seed (NDES) is evaluated in comparison to systemic or direct intratumoral administration. The NDES achieves sustained drug release through diffusion by leveraging electrostatic nanoconfinement within nanochannels, without requiring internal or external actuation. Using the 4T1 murine mammary carcinoma model, the biodistribution of Alexa Fluor-700 conjugated CD40 mAb is tracked via fluorescence imaging analysis, comparing three routes of administration over 7 and 14 days. NDES-treated cohort shows sustained high levels of intratumoral CD40 mAb without off-target organ exposure, compared to the intraperitoneal and direct intratumoral administration. Moreover, radiation pre-treatment of the 4T1 tumors augments tumor retention of CD40 mAb in the NDES group. Overall, sustained intratumoral release of CD40 mAb via the NDES improves local drug bioavailability without systemic dissemination, suggesting an enhanced approach for immunotherapy administration.

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Skeletal muscle atrophy is a critical health problem that affects quality of life and increases morbidity and mortality. At present, exercise training remains the only intervention and pharmaceutical treatments remain elusive. Formoterol (FMT), a 2-adrenergic receptor agonist, has emerged as a potential therapeutic by triggering skeletal muscle anabolism with daily dosing. Here, the efficacy of sustained FMT release is investigated via a subcutaneously implanted nanofluidic delivery system (nF) to prevent muscle wasting. Pharmacokinetics of nF-mediated sustained FMT delivery (nF-FMT) in healthy mice is assessed for 56 days, which demonstrates an anabolic effect on skeletal muscles. Using a hind limb suspension unloading mouse model, it is shown that nF-FMT treatment attenuates soleus mass loss in comparison to control mice. Further, the very first study of an implantable drug delivery device in microgravity in vivo is launched. The microgravity environment aboard the International Space Station is leveraged to assess the atrophy prevention capability of nF-FMT in mice for 29 and 55 days. Muscle hypertrophy is observed in both ground control and spaceflight mice treated with nF-FMT compared to their respective vehicle controls. Overall, the nF system is presented as a viable platform for sustained delivery of FMT for therapeutic intervention of skeletal muscle atrophy.

37 Background: Immune related adverse events still occur in up to 91% of patients receiving immunotherapy. Intratumoral administration is a potential solution to limit these events by reducing systemic exposure while increasing local concentration. However, intratumoral injection is hindered by rapid clearance of drug from the tumor. Our group has developed an intratumoral nanochannel implant for sustained delivery of immunotherapy (NDES) as a solution. Recent clinical and preclinical studies have found success in the combination of radiotherapy and immunotherapy in improving both local and distant tumor response. We propose a combination of radiotherapy followed by sustained intratumoral delivery of immunotherapy as a treatment regimen to improve tumor response and reduce side effects. Methods: Mice were implanted with the 4T1 murine mammary carcinoma and separated into treatment and control groups. CD40 agonist antibody was delivered intratumorally via NDES. Radiotherapy was administered at 8 Gy for three consecutive days and implantation of the NDES occurred the day after the final fraction of radiation. The tumor growth curve was plotted and tumor, spleen, lymph nodes, lungs, and blood were collected at the study endpoint for further flow cytometry and histological analysis. Results: The combination of radiotherapy and sustained intratumoral CD40 antibody showed significantly decreased tumor growth rates over radiotherapy or sustained intratumoral immunotherapy alone. Both intratumoral and systemic T-cell activation was observed. Mice treated with sustained intratumoral CD40 antibody showed decreased toxicity when compared to those receiving comparable systemic dosage. Conclusions: Radiotherapy combined with local sustained intratumoral immunotherapy is a potential strategy for improving treatment of solid tumors which currently show suboptimal response to current immunotherapy regimens and for inducing a systemic response to distant metastases while minimizing adverse side effects. The sustained delivery profile of the NDES presents an opportunity for practical intratumoral administration and avoidance of repeated invasive procedures in patients.