Pdx Pharmaceuticals, Llc

LAKE OSWEGO, OR, United States

Pdx Pharmaceuticals, Llc

LAKE OSWEGO, OR, United States
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Patent
Pdx Pharmaceuticals, Llc and Oregon Health And Science University | Date: 2017-02-10

Disclosed herein are nanoconstructs comprising a nanoparticle, coated with additional agents such as cationic polymers, stabilizers, targeting molecules, labels, oligonucleotides and small molecules. These constructs may be used to deliver compounds to treat solid tumors and to diagnose cancer and other diseases. Further disclosed are methods of making such compounds and use of such compounds to treat or diagnose human disease.


Morry J.,Oregon Health And Science University | Ngamcherdtrakul W.,Oregon Health And Science University | Ngamcherdtrakul W.,Pdx Pharmaceuticals, Llc | Gu S.,Oregon Health And Science University | And 7 more authors.
Molecular Cancer Therapeutics | Year: 2017

Metastatic breast cancer is developed in about 20%to 30% of newly diagnosed patients with early-stage breast cancer despite treatments. Herein, we report a novel nanoparticle platform with intrinsic antimetastatic properties for the targeted delivery of Polo-like kinase 1 siRNA (siPLK1). We first evaluated it in a triple-negative breast cancer (TNBC) model, which shows high metastatic potential. PLK1 was identified as the top therapeutic target for TNBC cells and tumor-initiating cells in a kinomewide screen. The platform consists of a 50-nm mesoporous silica nanoparticle (MSNP) core coated layer-by-layer with bioreducible cross-linked PEI and PEG polymers, conjugated with an antibody for selective uptake into cancer cells. siRNA is loaded last and fully protected under the PEG layer from blood enzymatic degradation. The material has net neutral charge and low nonspecific cytotoxicity. We have also shown for the first time that the MSNP itself inhibited cancer migration and invasion in TNBC cells owing to its ROS- and NOX4-modulating properties. In vivo, siPLK1 nanoconstructs (six doses of 0.5 mg/kg) knocked down about 80% of human PLK1 mRNA expression in metastatic breast cancer cells residing in mouse lungs and reduced tumor incidence and burden in lungs and other organs of an experimental metastasis mouse model. Long-term treatment significantly delayed the onset of death in mice and improved the overall survival. The platform capable of simultaneously inhibiting the proliferative and metastatic hallmarks of cancer progression is unique and has great therapeutic potential to also target other metastatic cancers beyond TNBC. © 2017 American Association for Cancer Research.


Gu S.,Oregon Health And Science University | Hu Z.,Oregon Health And Science University | Ngamcherdtrakul W.,Oregon Health And Science University | Ngamcherdtrakul W.,Pdx Pharmaceuticals, Llc | And 7 more authors.
Oncotarget | Year: 2016

HER2 is overexpressed in about 20% of breast cancers and contributes to poor prognosis. Unfortunately, a large fraction of patients have primary or acquired resistance to the HER2-targeted therapy trastuzumab, thus a multi-drug combination is utilized in the clinic, putting significant burden on patients. We systematically identified an optimal HER2 siRNA from 76 potential sequences and demonstrated its utility in overcoming intrinsic and acquired resistance to trastuzumab and lapatinib in 18 HER2-positive cancer cell lines. We provided evidence that the drug-resistant cancer maintains dependence on HER2 for survival. Importantly, cell lines did not readily develop resistance following extended treatment with HER2 siRNA. Using our recently developed nanoparticle platform, systemic delivery of HER2 siRNA to trastuzumab-resistant tumors resulted in significant growth inhibition. Moreover, the optimal HER2 siRNA could also silence an exon 16 skipped HER2 splice variant reported to be highly oncogenic and linked to trastuzumab resistance.


Morry J.,Oregon Health And Science University | Ngamcherdtrakul W.,Oregon Health And Science University | Gu S.,Oregon Health And Science University | Goodyear S.M.,Oregon Health And Science University | And 6 more authors.
Biomaterials | Year: 2015

Fibrotic diseases such as scleroderma have been linked to increased oxidative stress and upregulation of pro-fibrotic genes. Recent work suggests a role of NADPH oxidase 4 (NOX4) and heat shock protein 47 (HSP47) in inducing excessive collagen synthesis, leading to fibrotic diseases. Herein, we elucidate the relationship between NOX4 and HSP47 in fibrogenesis and propose to modulate them altogether as a new strategy to treat fibrosis. We developed a nanoparticle platform consisting of polyethylenimine (PEI) and polyethylene glycol (PEG) coating on a 50-nm mesoporous silica nanoparticle (MSNP) core. The nanoparticles effectively delivered small interfering RNA (siRNA) targeting HSP47 (siHSP47) in an invitro model of fibrosis based on TGF-β stimulated fibroblasts. The MSNP core also imparted an antioxidant property by scavenging reactive oxygen species (ROS) and subsequently reducing NOX4 levels in the invitro fibrogenesis model. The nanoparticle was far superior to n-acetyl cysteine (NAC) at modulating pro-fibrotic markers. Invivo evaluation was performed in a bleomycin-induced scleroderma mouse model, which shares many similarities to human scleroderma disease. Intradermal administration of siHSP47-nanoparticles effectively reduced HSP47 protein expression in skin to normal level. In addition, the antioxidant MSNP also played a prominent role in reducing the pro-fibrotic markers, NOX4, alpha smooth muscle actin (α-SMA), and collagen type I (COL I), as well as skin thickness of the mice. © 2015 Elsevier Ltd.


Ngamcherdtrakul W.,Oregon Health And Science University | Ngamcherdtrakul W.,Pdx Pharmaceuticals, Llc | Castro D.J.,Oregon Health And Science University | Castro D.J.,Pdx Pharmaceuticals, Llc | And 6 more authors.
Cancer Treatment Reviews | Year: 2016

This Review discusses the various types of non-coding oligonucleotides, which have garnered extensive interest as new alternatives for targeted cancer therapies over small molecule inhibitors and monoclonal antibodies. These oligonucleotides can target any hallmark of cancer, no longer limited to so-called "druggable" targets. Thus, any identified gene that plays a key role in cancer progression or drug resistance can be exploited with oligonucleotides. Among them, small-interfering RNAs (siRNAs) are frequently utilized for gene silencing due to the robust and well established mechanism of RNA interference. Despite promising advantages, clinical translation of siRNAs is hindered by the lack of effective delivery platforms. This Review provides general criteria and consideration of nanoparticle development for systemic siRNA delivery. Different classes of nanoparticle candidates for siRNA delivery are discussed, and the progress in clinical trials for systemic cancer treatment is reviewed. Lastly, this Review presents HER2 (human epidermal growth factor receptor type 2)-positive breast cancer as one example that could benefit significantly from siRNA technology. How siRNA-based therapeutics can overcome cancer resistance to such therapies is discussed. © 2016 Elsevier Ltd.


Ngamcherdtrakul W.,Oregon Health And Science University | Morry J.,Oregon Health And Science University | Gu S.,Oregon Health And Science University | Castro D.J.,Oregon Health And Science University | And 11 more authors.
Advanced Functional Materials | Year: 2015

In vivo delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. A new nanoparticle construct that is engineered for efficient delivery of siRNA to tumors is now described. The construct comprises a 47-nm mesoporous silica nanoparticle core coated with a crosslinked polyethyleneimine-polyethyleneglycol copolymer, carrying siRNA against the human epidermal growth factor receptor type 2 (HER2) oncogene, and coupled to the anti-HER2 monoclonal antibody (trastuzumab). The construct is engineered to increase siRNA blood half-life, enhance tumor-specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti-HER2 nanoparticles produce apoptotic death in HER2 positive (HER2+) breast cancer cells grown in vitro, but not in HER2 negative (HER2-) cells. One dose of the siHER2-nanoparticles reduces HER2 protein levels by 60% in trastuzumab-resistant HCC1954 xenografts. Administration of multiple intravenous doses over 3 weeks significantly inhibits tumor growth (p < 0.004). The siHER2-nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch-to-batch reproducibility and the production methods are suitable for large-scale production. These results suggest that this siHER2-nanoparticle is ready for clinical evaluation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 299.74K | Year: 2012

DESCRIPTION (provided by applicant): Hyperphosphatemia is universal to end stage chronic kidney disease patients and a majority of dialysis patients totaling of 400,000 in the US and 2 million worldwide. Current oral phosphate binders to treat hyperphosphatemia still have many drawbacks, including a high risk of calcification, high costs ( 2100- 6500 per patient a year), low-to-moderate efficacy, gastrointestinal adverse effects, and high pill burdens (500-800 mg tablet, 3-12 tablets a day). These lead to low pill compliance, a major reason why patients fail to manage their hyperphosphatemia, which can be fatal. To address the medical need, PDX Pharmaceuticals, LLC is applying for an STTR Phase I grant for the development of a novel oral phosphate binder. Although this class of drugs generates ~ 1.4 billion USD a year in 2009 revenues, new RandD in search for the better drugs is lacking, lagging behind the state of technology. Innovation in this project lies in the utilization of our nanotechnology and ligand design expertise to revolutionize oral phosphate binders. Our goal is to develop a next generation drug with reduced costs, increased patients' compliance (by lowering pill burden and gastrointestinal side effects), and reduced drug associated risks. This Phase I project will involve bench-scale formulating of our iron functionalized silica (Fe-SAMMS), followed by efficacy and safety evaluations both in vitro and in rodent models against the standard of care drugs. Our preliminary studies show that Fe-SAMMS has a phosphate binding ability that is not dependent on pH or other competing anions relevant to gastrointestinal tract, is composed of benign chemicals including silica, iron, and, ethylenediamine- polysiloxane, and is virtually not soluble or absorbed to the body when tested in renal failure rats. SAMMS is readily scaled up within an existing manufacturing base, has a long shelf-life of over 8 years, and low production costs. This project will be a collaborative work between PDX Pharmaceuticals (an OHSU spin-off company) for material development and optimization, and OHSU for in vivo efficacy and safety evaluations by exploiting state of the art animal facilities and clinical expertise at OHSU. Results will lay a foundation for Phase II, intended forlarge-scale GMP production of the Fe-SAMMS, and its GLP safety evaluation toward the IND filing. Our strong team consists of the innovator and developer of SAMMS for metal capture in humans (Yantasee); an Associate Professor of OHSU (Gruber, MD), who has along track record of drug evaluations in animals and moving drugs through the FDA processes; the former Chair of the Nephrology of the American Board of Internal Medicine (Anderson, MD); and a partner at Battelle Ventures (Warren), who specializes in commercialization of health and life science technologies coming out of Battelle's operated National Laboratories. We enjoy strong support from Battelle-PNNL and OHSU who co-own the IP right to be licensed to us, and the Oregon Nanoscience and Microtechnologies Institute (ONAMI), who is about to grant us initial gap funding for commercialization of this technology. Therefore, we fully anticipate a high chance of success for this project. PUBLIC HEALTH RELEVANCE: We propose to develop a novel calcium-free oral phosphate binder to treat hyperphosphatemia in end stage chronic kidney disease patients. The new drug is aimed to have higher efficacy, less pill burden, lower costs, and less adverse effects, resultin in higher pill adherence than the current drugs.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 200.00K | Year: 2013

Over one million women worldwide are diagnosed with breast cancer each year. Roughly 20% of all breast cancers overexpress the human epidennal growth receptor 2 (HER2-positive subtype). HER2-targeted therapies, including Herceptin and lapatinib, account for 55% of the breast cancer therapy market in 2011 (or 5 billion annually). Response to HER2-targeted therapies typically average about one year due to developed resistance. This represents an area of unmet clinical need. HER2 over-expression has been clearly linked to aggressive and abnonnal tumor growth, rapid metastases, and drug resistance in this cancer subtype. siRNA for knocking down HER2 offers a new treatment modality to overcome drug resistance. We are developing a novel nanoparticle platform fortherapeutic siRNA delivery. Novelty lies in the hybrid polymeric-inorganic nanoparticles that take full advantage of both classes of materials to overcome siRNA delivery barriers (e.g., poor bioavailability, poor cellular uptake, and off-target effects) and enable large-scale manufacturing of the nanocontruct. This Phase I portion will optimize the nanoparticle platforms to achieve gt70% knockdown ofHER2 in three HER2-positive breast cancer cell lines, leading to programmed death of the cancer cells, whilehaving no adverse effect on HER2-negative cells or nonnal cells. The most optimized nanoparticle platform will undergo further in vivo evaluation in Phase II SBIR project. PUBLIC HEALTH RELEVANCE

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