Priya Jain

Sustained Administration of Hormones Exploiting Nanoconfined Diffusion through Nanochannel Membranes

Implantable devices may provide a superior means for hormone delivery through maintaining serum levels within target therapeutic windows. Zero-order administration has been shown to reach an equilibrium with metabolic clearance, resulting in a constant serum concentration and bioavailability of released hormones. By exploiting surface-to-molecule interaction within nanochannel membranes, it is possible to achieve a long-term, constant diffusive release of agents from implantable reservoirs. In this study, we sought to demonstrate the controlled release of model hormones from a novel nanochannel system. We investigated the delivery of hormones through our nanochannel membrane over a period of 40 days. Levothyroxine, osteocalcin and testosterone were selected as representative hormones based on their different molecular properties and structures. The release mechanisms and transport behaviors of these hormones within 3, 5 and 40 nm channels were characterized. Results further supported the suitability of the nanochannels for sustained administration from implantable platforms.

Unexpected behaviors in molecular transport through size-controlled nanochannels down to the ultra-nanoscale

Ionic transport through nanofluidic systems is a problem of fundamental interest in transport physics and has broad relevance in desalination, fuel cells, batteries, filtration, and drug delivery. When the dimension of the fluidic system approaches the size of molecules in solution, fluid properties are not homogeneous and a departure in behavior is observed with respect to continuum-based theories. Here we present a systematic study of the transport of charged and neutral small molecules in an ideal nanofluidic platform with precise channels from the sub-microscale to the ultra-nanoscale (<5 nm). Surprisingly, we find that diffusive transport of nano-confined neutral molecules matches that of charged molecules, as though the former carry an effective charge. Further, approaching the ultra-nanoscale molecular diffusivities suddenly drop by up to an order of magnitude for all molecules, irrespective of their electric charge. New theoretical investigations will be required to shed light onto these intriguing results.Transport through nanochannels is usually dominated by electrostatic interactions and depends on the charge of diffusing molecules. Here the authors show that for channel heights between 2 and 4 nanometers, transport is insensitive to molecule charge.

A pharmacokinetic study of GC-1 delivery using a nanochannel membrane device

This study demonstrated a nanochannel membrane device (NMD) for controlled and sustained release of GC-1 in rats, in the context of the treatment of metabolic syndrome. Release profiles were established in vitro both with and without 5% labrasol for over 2 months. In vivo pharmacokinetic evaluation showed effective GC-1 plasma concentrations, which resulted in significant reductions in body weight after just one week of treatment when compared to the NMD releasing vehicle only (PBS). We also provided evidence that rats treated with NMD-GC-1 present sub-active thyroids and clear differences in the morphology of the epithelium and follicles as compared to the controls, while the heart showed changes in weight. Moreover, body temperatures remained stable throughout treatment, and glucose, pancreatic islet size, and liver histology appeared similar between the treated and control groups. Prolonged constant administration of GC-1 from the NMD proved to be a valid strategy to facilitate weight loss.

Transcutaneously refillable nanofluidic implant achieves sustained level of tenofovir diphosphate for HIV pre-exposure prophylaxis

ABSTRACT 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. Graphical abstract Figure. No caption available. HighlightsRefillable nanofluidic implant achieves preventive level of tenofovir diphosphate for HIV pre‐exposure prophylaxis.

Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer

ABSTRACT Conventional systemic immunotherapy administration often results in insufficient anti‐tumor immune response and adverse side effects. Delivering immunotherapeutics intratumorally could maximize tumor exposure, elicit efficient anti‐tumor immune response, and minimize toxicity. To fulfill the unmet clinical need for sustained local drug delivery and to avoid repeated intratumoral injections, we developed a nanofluidic‐based device for intratumoral drug delivery called the nanofluidic drug‐eluting seed (NDES). The NDES is inserted intratumorally using a minimally invasive trocar method similar to brachytherapy seed insertion and offers a clinical advantage of drug elution. Drug diffusion from the NDES is regulated by physical and electrostatic nanoconfinement, thereby resulting in constant and sustained immunotherapeutic delivery without the need for injections or clinician intervention. In this study, the NDES was used to deliver immunotherapeutics intratumorally in the 4T1 orthotopic murine mammary carcinoma model, which recapitulates triple negative breast cancer. We demonstrated that NDES‐mediated intratumoral release of agonist monoclonal antibodies, OX40 and CD40, resulted in potentiation of local and systemic anti‐tumor immune response and inhibition of tumor growth compared to control mice. Further, mice treated with NDES‐CD40 demonstrated minimal liver damage compared to systemically treated mice. Collectively, our study highlights the NDES as an effective platform for sustained intratumoral immunotherapeutic delivery. The potential clinical impact is tremendous given that the NDES is applicable to a broad spectrum of drugs and solid tumors.

Efficacy of sustained delivery of GC-1 from a Nanofluidic system in a spontaneously obese non-human primate: a case study

With nearly 40% of U.S. adults obese, and childhood and adolescent rates rising, obesity and associated comorbidities are serious public health concerns with massive societal costs. Often, lifestyle interventions do not offer sufficient weight loss to improve health, requiring surgery and medications as adjunct management strategies. Here, we present a 4-month case study in which the sustained, low-dose, and constant administration of the thyroid receptor β selective agonist GC-1 (sobetirome) from a novel nanochannel membrane implant was assessed in an obese, pre-diabetic rhesus macaque. Dramatic loss of white adipose tissue in the abdomen from 36 to 18% was observed via magnetic resonance imaging in conjunction with normalized serum insulin and glycemia, with no signs of cardiotoxicity shown. The non-human primate study highlights sustained low-dose delivery of GC-1 from our minimally invasive subcutaneous implant as a valuable approach to induce weight loss and manage obesity and comorbidities, including type 2 diabetes.

Local and sustained delivery of tamoxifen for the prevention of ER+ breast cancer using a nanochannel delivery platform

A high incidence (∼75%) of primary breast cancers are estrogen receptor positive (ER+), and a large fraction of these patients can pursue chemopreventive therapies. However, due to adverse side effects, only 5% to 20% of the women at high risk who could benefit from chemotherapeutics enroll in preventive treatment. There is a clear need for alternative preventive strategies that minimize side effects and improve enrollment and compliance. Selective estrogen receptor modulators, such as tamoxifen (TMX), have been shown to reduce ER+ breast cancer incidence by up to 50% among high-risk women. Importantly, along with raloxifene, it is one of only two FDA-approved drugs for breast cancer prevention. TMX has been in use for over 40 years and has a proven record in pre- and post-menopausal women. However, the drug is marred by side effects, the most common being symptoms of menopause. Further, women treated systemically and chronically with TMX were found to have an increased incidence of endometrial carcinoma. Although rare, this side effect, along with other serious adverse effects (such as blood clots, strokes, and cataracts), has resulted in a debate concerning TMX use in cancer prevention. As the key for breast cancer chemoprevention relies upon long-term delivery of drugs while circumventing side effects, we have developed a novel local delivery strategy for the constant and sustained administration of TMX. We maintain a long-term, local release of TMX in mammary tissues by utilizing a novel implantable nanochannel Delivery System (nDS). The nDS consists of a bioinert, implantable, and mechanically robust silicon membrane which houses an exact number of densely packed slit-nanochannels as small as 2.5 nm with tight tolerances on size, geometry, and surface properties. Providing steady levels of TMX at the mammary gland target through nDS delivery maximizes the therapeutic index while limiting the unwanted secondary effects, which will ultimately improve patient compliance. In this work we chemically induced tumorigenesis in Sprague-Dawley rats by N-methyl-N-nitrosourea (NMU) injection to promote development of estrogen-dependent tumors. We performed ovariectomies seven days after NMU injection to mimic post-menopausal biology. nDS implants loaded with either TMX or PEG400 (negative control) were inserted under the left abdominal mammary gland to determine effects of nDS-TMX on tumor growth and biomarkers. Utilizing LC/MS we were able to determine the amount of TMX released from the nDS. Rats were examined for palpable tumors to assess breast tumor incidence, latency to onset, and multiplicity. Our results show that the nDS implant enables the effective delivery of TMX in this breast tumor model. Further, this technology has the potential to rapidly provide long-term breast cancer protection with significant improvement in the quality of life of patients at high risk, thereby saving thousands of lives every year. Citation Format: Carly S. Filgueira, Eugenia Nicolov, Andrea Ballerini, R. Lyle Hood, Priya Jain, Giacomo Bruno, Alessandro Grattoni. Local and sustained delivery of tamoxifen for the prevention of ER+ breast cancer using a nanochannel delivery platform. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1320.