Oak Crest Institute of Science

Foothill Ranch, CA, United States

Oak Crest Institute of Science

Foothill Ranch, CA, United States
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Moss J.A.,Oak Crest Institute of Science | Baum M.M.,Oak Crest Institute of Science | Easley J.T.,Colorado State University | Cox D.M.,Oak Crest Institute of Science | Smith T.J.,Auritec Pharmaceuticals, Inc.
PLoS ONE | Year: 2017

Two recent Phase III clinical trials to investigate an intravaginal ring for preventing HIV infection demonstrated that adherence to prescribed device use was a primary driver of efficacy. Surrogate methods for determining adherence in the studies were limited in their inability to monitor temporal patterns of use and allow deconvolution of the effects of adherence and device efficacy on HIV infection rates. To address this issue, we have developed functionality in an intravaginal ring to continuously monitor when the device is being used and maintain a log of adherence that can be accessed by clinicians after it is removed. An electronic module fabricated with common, inexpensive electronic components was encapsulated in a silicone intravaginal ring. The device uses temperature as a surrogate measure of periods of device insertion and removal, and stores a record of the data for subsequent retrieval. The adherence-monitoring intravaginal ring accurately recorded the device status over 33 simulated IN-OUT cycles and more than 1000 measurement cycles in vitro. Following initial in vitro testing in a temperature-controlled chamber, the device was evaluated in vivo in sheep using a predetermined insertion/removal pattern to simulate intravaginal ring use. After insertion into the vaginal cavity of a sheep, the logged data correctly indicated the device status over 29 hours of continuous measurement including three cycles of insertion and removal. The device described here is a promising, low-cost method for real-time adherence assessment in clinical trials involving medicated intravaginal rings or other intravaginal devices. © 2017 Moss et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

News Article | March 22, 2016
Site: www.nanotech-now.com

Abstract: A team of researchers led by Caltech scientists have shown that nanoparticles can function to target tumors while avoiding adjacent healthy tissue in human cancer patients. "Our work shows that this specificity, as previously demonstrated in preclinical animal studies, can in fact occur in humans," says study leader Mark E. Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering at Caltech. "The ability to target tumors is one of the primary reasons for using nanoparticles as therapeutics to treat solid tumors." The findings, published online the week of March 21, 2016 in the journal Proceedings of the National Academy of Sciences, demonstrate that nanoparticle-based therapies can act as a "precision medicine" for targeting tumors while leaving healthy tissue intact. In the study, Davis and his colleagues examined gastric tumors from nine human patients both before and after infusion with a drug -- camptothecin -- that was chemically bound to nanoparticles about 30 nanometers in size. "Our nanoparticles are so small that if one were to increase the size to that of a soccer ball, the increase in size would be on the same order as going from a soccer ball to the planet Earth," says Davis, who is also a member of the City of Hope Comprehensive Cancer Center in Duarte, California, where the clinical trial was conducted. The team found that 24 to 48 hours after the nanoparticles were administered, they had localized in the tumor tissues, released their drug cargo, and the drug had the intended biological effects of inhibiting two proteins that are involved in the progression of the cancer. Equally important, both the nanoparticles and the drug were absent from healthy tissue adjacent to the tumors. The nanoparticles are designed to be flexible delivery vehicles. "We can attach different drugs to the nanoparticles, and by changing the chemistry of the bond linking the drug to the nanoparticle, we can alter the release rate of the drug to be faster or slower," says Andrew Clark, a graduate student in Davis's lab and the study's first author. Davis says his team's findings are suggestive that a phenomenon known as the enhanced permeability and retention (EPR) effect is at work in humans. In the EPR effect, abnormal blood vessels that are "leakier" than normal blood vessels in healthy tissue allow nanoparticles to preferentially concentrate in tumors. Until now, the existence of the EPR effect has been conclusively proven only in animal models of human cancers. "Our results don't prove the EPR effect in humans, but they are completely consistent with it," Davis says. The findings could also help pave the way toward more effective cancer drug cocktails that can be tailored to fight specific cancers and that leave patients with fewer side effects. "Right now, if a doctor wants to use multiple drugs to treat a cancer, they often can't do it because the cumulative toxic effects of the drugs would not be tolerated by the patient," Davis says. "With targeted nanoparticles, you have far fewer side effects, so it is anticipated that drug combination can be selected based on the biology and medicine rather than the limitations of the drugs." In addition to Davis and Clark, other coauthors on the study, entitled "CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing," include Devin Wiley (MS '11, PhD '13) and Jonathan Zuckerman (PhD '12); Paul Webster of the Oak Crest Institute of Science; Joseph Chao and James Lin at City of Hope; and Yun Yen of Taipei Medical University, who was at City of Hope and a visitor in the Davis lab at the initiation of the clinical trial. The research was supported by grants from the National Cancer Institute and the National Institutes of Health and by Cerulean Pharma Inc. Davis is a consultant to and holds stock in Cerulean Pharma Inc. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.

Moss J.A.,Oak Crest Institute of Science | Srinivasan P.,Centers for Disease Control and Prevention | Smith T.J.,Oak Crest Institute of Science | Smith T.J.,Auritec Pharmaceuticals, Inc. | And 7 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

Preexposure prophylaxis using oral regimens involving the HIV nucleoside reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) demonstrated efficacy in three clinical trials. Adherence was determined to be a key parameter for success. Incorporation of the TDF-FTC combination into intravaginal rings (IVRs) for sustained mucosal delivery could increase product adherence and efficacy compared with those of oral and vaginal gel formulations. A novel pod-IVR technology capable of delivering multiple drugs is described; this constitutes the first report of an IVR delivering TDF and FTC, as well as a triple-combination IVR delivering TDF, FTC, and the entry inhibitor maraviroc (MVC). The pharmacokinetics and preliminary local safety of the two combination pod-IVRs were evaluated in the pig-tailed macaque model. The devices exhibited sustained release at controlled rates over the 28-day study period. Median steady-state drug levels in vaginal tissues in the TDF-FTC group were 30 μg g-1 (tenofovir [TFV], in vivo hydrolysis product of TDF) and 500 μg g-1 (FTC) and in the TDF-FTC-MVC group were 10 μg g-1 (TFV), 150 μg g-1 (FTC), and 20 μg g -1 (MVC). No adverse events were observed, and there were no toxicological findings. Mild-to-moderate increases in inflammatory infiltrates were observed in the vaginal tissues of some animals in both the presence and the absence of the IVRs. The IVRs did not disturb the vaginal microbiota, and levels of proinflammatory cytokines remained stable throughout the study. Pod-IVR candidates based on the TDF-FTC combination have potential for the prevention of vaginal HIV acquisition and merit clinical investigation. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Cortez J.M.,Auritec Pharmaceuticals, Inc. | Quintero R.,Auritec Pharmaceuticals, Inc. | Moss J.A.,Oak Crest Institute of Science | Beliveau M.,Pharsight | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015

Mother-to-child transmission (MTCT) of HIV-1 remains a global health problem. The World Health Organization (WHO) recommendations advise the administration of a once-daily, oral, prophylactic regimen of the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) from birth until 4 to 6 weeks of age for infants born to HIV-infected mothers in regions without access to safe and nutritionally adequate alternatives to breast milk. A critical factor driving the successful implementation of the WHOguidelines involves sustaining high adherence to the frequent dosing. With these challenges in mind, we have developed the first injectable, sustained-release NVP formulations with the goal of providing, for 6 weeks or longer, preventative plasma drug levels from a single subcutaneous administration at birth. The long-acting NVP consists of large (>50 μm), monodisperse NVP particles coated with biocompatible polymers that control the drug release kinetics. Two lead formulations exhibiting burst-free, sustained-release kinetics for up to 75 days in vitro were developed. Subsequent in vivo studies in rats demonstrated no toxicity related to the formulations. Rat plasma NVP concentrations were above the analytical assay's limit of quantification for up to 28 days. Pharmacokinetic analysis of the rat plasma NVP concentration-time data allowed absorption rate constants to be calculated. These data then were used to simulate infant NVP exposure from a single injected dose (<200 mg) of our longacting formulations, demonstrating preliminary feasibility of the technology to maintain safe, preventative NVP plasma levels (0.2 to 3.0 μgml-1) for 6 weeks or longer. © 2015 American Society for Microbiology. All Rights Reserved.

Gunawardana M.,Oak Crest Institute of Science | Remedios-Chan M.,Auritec Pharmaceuticals, Inc. | Miller C.S.,Oak Crest Institute of Science | Fanter R.,Oak Crest Institute of Science | And 8 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015

Oral or topical daily administration of antiretroviral (ARV) drugs to HIV-1-negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention. Adherence to the dosing regimen has emerged as a critical factor determining efficacy outcomes of clinical trials. Because adherence to therapy is inversely related to the dosing period, sustained release or long-acting ARV formulations hold significant promise for increasing the effectiveness of HIV-1 preexposure prophylaxis (PrEP) by reducing dosing frequency. A novel, subdermal implant delivering the potent prodrug tenofovir alafenamide (TAF) with controlled, sustained, zero-order (linear) release characteristics is described. A candidate device delivering TAF at 0.92 mg day-1 in vitro was evaluated in beagle dogs over 40 days for pharmacokinetics and preliminary safety. No adverse events related to treatment with the test article were noted during the course of the study, and no significant, unusual abnormalities were observed. The implant maintained a low systemic exposure to TAF (median, 0.85 ng ml-1; interquartile range [IQR], 0.60 to 1.50 ng ml-1) and tenofovir (TFV; median, 15.0 ng ml-1; IQR, 8.8 to 23.3 ng ml-1), the product of in vivo TAF hydrolysis. High concentrations (median, 512 fmol/106 cells over the first 35 days) of the pharmacologically active metabolite, TFV diphosphate, were observed in peripheral blood mononuclear cells at levels over 30 times higher than those associated with HIV-1 PrEP efficacy in humans. Our report on the first sustained-release nucleoside reverse transcriptase inhibitor (NRTI) for systemic delivery demonstrates a successful proof of principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Moss J.A.,Oak Crest Institute of Science | Malone A.M.,Auritec Pharmaceuticals, Inc. | Smith T.J.,Oak Crest Institute of Science | Smith T.J.,Auritec Pharmaceuticals, Inc. | And 6 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

Multipurpose technologies that simultaneously protect from sexually transmitted infections and unintended pregnancy are urgently needed. Pod-intravaginal rings (IVRs) formulated with the antiretroviral agents (ARVs) tenofovir, nevirapine, and saquinavir and the contraceptives etonogestrel and estradiol were evaluated in sheep. Steady-state concentrations were maintained for 28 days with controlled, sustained delivery. This proof-of-principle study demonstrates that pod IVRs can deliver three ARVs from different mechanistic classes and a progestin-estrogen combination over the wide range needed for putative preventative efficacy. © 2013, American Society for Microbiology. All Rights Reserved.

Gunawardana M.,Oak Crest Institute of Science | Mullen M.,Oak Crest Institute of Science | Yoo J.,Oak Crest Institute of Science | Webster P.,Oak Crest Institute of Science | And 2 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

Topical administration of live commensal bacteria to the vaginal tract holds significant potential as a cost-effective strategy for the treatment of sexually transmitted infections and the delivery of mucosal vaccines. Probiotic-releasing intravaginal rings (IVRs) embody significant theoretical advantages over traditional daily-dosage forms, such as sustained and controlled delivery leading to improved adherence to therapy compared to that of frequent dosing. The conventional IVR designs, however, are not amenable to the delivery of live bacteria. We have developed a novel pod-IVR technology where polymer-coated tablets ("pods") of Lactobacillus gasseri strain ATCC 33323, a commensal microorganism of human origin, are embedded in silicone IVRs. The release rate of bacterial cells is controlled by the diameter of a delivery channel that exposes a portion of the pod to external fluids. In vitro studies demonstrated that the prototype devices released between 1.1 × 10 7 and 14 × 107 cells per day for up to 21 days in a controlled sustained fashion with stable burst-free release kinetics. The daily release rates were correlated with the cross-sectional area of the delivery channel. Bacteria in the IVR pods remained viable throughout the in vitro studies and formed biofilms on the surfaces of the devices. This proof-of-principle study represents the first demonstration of a prolonged, sustained release of bacteria from an intravaginal device and warrants further investigation of this device as a nonchemotherapeutic agent for the restoration and maintenance of normal urogenital flora. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Hoffmann M.R.,California Institute of Technology | Moss J.A.,Oak Crest Institute of Science | Baum M.M.,Oak Crest Institute of Science
Dalton Transactions | Year: 2011

Carbon dioxide is an appealing renewable feedstock for industrial chemical processes. This does not mean, however, that all chemical processes using CO2 are environmentally-friendly. Perspectives on the sustainability of CO2 utilization and artificial photosynthesis are provided. The discussions focus on the photocatalytic production of Cx (x ≥ 2) compounds, where all the carbon in the products is derived from CO2. This area of research, while promising, has received far less attention than analogous systems leading to C1 products. © 2011 The Royal Society of Chemistry.

A method of identifying a biofilm that includes non-typeable Haemophilus influenza (NTHi) including a step of screening a sample for the presence of one or more biofilm-specific proteins that are expressed by NTHi. In some cases, an NTHi biofilm-related disease in a subject is diagnosed. Also disclosed are protein microarrays for screening biofilm-specific proteins in a sample, formulations comprising one or more biofilm-specific proteins or fragments thereof, and methods for inducing an immune response in a patient against a biofilm-related infection.

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 211.86K | Year: 2013

DESCRIPTION (provided by applicant): The broad long-term of this project is to develop methods for evaluation of adherence to intravaginal microbicide therapy for the prevention of HIV transmission. Correct determination of adherence to preventative therapies in clinical trials is essential to accurate evaluation of efficacy. A better understanding of the true adherence to a preventative therapy will lead to the development of products with higher acceptability, and provide insight into the relationship between self-reported use of preventative therapy and actual use. Current methods of adherence evaluation for vaginal microbicide trials include self-reporting by study participants, physician or health care provider assessment, and inspection of study materials (gel applicators or used intravaginal rings) returned during clinic visits. All of these methods are prone to inaccuracy as indicated by the over-reporting of adherence observed in several clinical trials when adherence metrics were compared to trial outcomes. The proposed adherence-monitoring intravaginal ring (adherence IVR) will allow the direct measurement of adherence to IVR-delivered microbicide therapy by monitoring IVR temperature, conductivity, or both continuously on a half-hourly to hourly timescale to determine if the IVR is being worn or not during a clinical trial. The adherence IVR will contain a miniaturized module for sensing temperature (IVR at body temperature when in and below when out) and conductivity (IVR wetted and conductivity high when in, IVR dry and conductivity low when out) to determine adherence state. A microcontroller circuit embedded completely in the silicone ring structure will process the sensor data and store a digital adherence state (1 = IVR in, 0 = IVR out) to non-volatile memory at a fixed time interval. When the ring is removed, typically monthly, the adherence data may be downloaded from the IVR to a laptop computer or other device (smart phone or tablet) to provide a record of adherence that is free from reporting bias. The project has three principal objectives: (1) development of the microcontroller and sensor electronics and embedded software for sensor signal processing, conversion to digital adherence values, and logging to non-volatile memory for subsequentretrieval; (2) incorporation of this adherence monitoring functionality into a pod-IVR for intravaginal delivery of the microbicide tenofovir; and (3) evaluation of adherence monitoring performance, preliminary safety, and pharmacokinetics of tenofovir delivery in a sheep model. At the conclusion of this Phase I effort, a novel method for evaluating adherence to IVR microbicide therapy for prevention of HIV transmission will have been designed, fabricated, and evaluated in an animal model. The adherence-monitoring technology developed here may be extended to other pod-IVR delivery devices (i.e. microbicide combinations) and other IVR platforms. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: This project aims to develop a novel method for assessing adherence to intravaginal ring (IVR)-based microbicide therapy for the prevention of HIV transmission in clinical trial settings. The proposed adherence IVR will utilize measurement of temperatore, conductivity, or both in combination to determine if the ring is being worn or not, and to log a continuous, digital record of adherence determination for subsequent retrieval at the study conclusion.

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