Characterization of pegylated and non-pegylated liposomal formulation for the delivery of hypoxia activated vinblastine-N-oxide for the treatment of solid tumors

(March 14, 2017) –  Journal of Controlled Release

Abstract – Solid tumors often contain hypoxic regions which are resistant to standard chemotherapy and radiotherapy. We
have developed a liposomal delivery system for a prodrug of vinblastine (CPD100) which converts to the parent
compound only in the presence of lower oxygen levels. As a part of this work we have developed and optimized
two formulations of CPD100: one composed of sphingomyelin/cholesterol (55/45; mol/mol) (CPD100Li) and the
other composed of sphingomyelin/cholesterol/PEG (55/40/5; mol/mol) (CPD100 PEGLi). We evaluated the antiproliferative
effect of CPD100 and the two formulations against A549 non-small lung cancer cell. A549 cell line
showed to be sensitive to CPD100 and the two formulations displayed a higher hypoxic: air cytotoxicity ratio
compared to the pro-drug. CPD100 elimination from the circulation after injection in mouse was characterized
by a very short circulation time (~0.44 h), lower area under the curve (AUC) (33 μg h/mL) and high clearance
(916 mL/h/kg) and lower volume of distribution (17.4 mL/kg).Total drug elimination from the circulation after
the administration of liposomal formulation was characterized by prolonged circulation time (5.5 h) along
with increase in the AUC (56 μg h/mL) for CPD100 Li and (9.5 h) with AUC (170 μg h/mL) for CPD100PEGLi.
This was observed along with increase in volume of distribution and decrease in clearance for the liposomes.
The systemic exposure of the free drug was much lower than that achieved with the liposomes. When evaluated
for the efficacy in A549 xenograft model in mice, both the liposomes demonstrated excellent tumor suppression
and reduction for 3 months. The blood chemistry panel and the comprehensive blood analysis showed no increase
or decrease in the markers and blood count. In summary, the pharmacokinetic analysis along with the ef-
ficacy data emphasis on how the delivery vehicle modifies and enhances the accumulation of the drug and at the
same time the increased systemic exposure is not related to toxicity.

New drug delivery system could help fight tumors

(April 4, 2017) – Researchers at Oregon State University have developed a new cancer-drug delivery system that may help overcome the challenge of treating solid tumors often resistant to treatment.

Carcinomas, a type of cancer that affect the lung, prostate, colon and breast, are solid tumors that contain hypoxic or low oxygen regions that cause slow growth and resistance to drug treatment to shrink or kill the tumor.

The team at Oregon State found a way to use a prodrug, a pharmacologically inactive compound that is metabolized by the body into an active drug, to overcome the hypoxia of carcinoma tumors.

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Researchers developed two different lipid-based platform formulations called liposomes using the prodrug vinblastine-N-oxide to carry the prodrug to the tumor’s hypoxic regions. This approach proved safe and more effective than the drug delivered without a liposome.

“The tumor model we chose, lung cancer, is one of the very well established tumors and there’s a very strong hypoxia associated with that — as well as, lung cancer is one of these cancers that in its advanced stages, it’s a terminal disease, and there’s a need for new treatments,” Adam Alani, of the OSU College of Pharmacy, said in a press release.

In mice models, researchers found the drug without any liposome showed some tumor suppression but mice that received the drug and liposome combination were healthy and tumor-free for nearly 100 days.

“The formulations clearly performed better than the unformulated drug as well as much better than Cisplatin, the standard-of-care drug for this research,” Alani said. “Now we’re collaborating with Cascade Prodrug and the College of Veterinary Medicine to assess safety and efficacy in dog models, and trying to look at other tumors, like bladder cancer, associated with dogs.”

New drug delivery system shows promise for fighting solid tumors

Portland, Ore. – (April 3, 2017) – A new cancer-drug delivery system shows the ability to exploit the oxygen-poor areas of solid tumors that make the growths resistant to standard chemotherapy and radiation treatment.

Carcinomas that affect the breast, lung, prostate and colon are among the solid-tumor cancers, as are malignancies in the lymphatic system, known as lymphomas, and the much less common sarcomas that arise in connective tissue.

These solid masses often contain hypoxic regions, where the concentration of oxygen in the tissue is low. Hypoxic cancer cells grow slowly, and that makes them less susceptible to the drugs prescribed to kill or damage them.

Researchers at Oregon State University have found a way to turn the tables on those cells using a “prodrug” loaded into nanostructured platforms.

A prodrug is a pharmacologically inactive compound that the body metabolizes into an active drug, in this case the cancer drug vinblastine.

Provided with the prodrug vinblastine-N-oxide by research partners at Cascade Prodrug Inc. of Eugene, Ore., OSU scientists developed two different lipid-based platform formulations known as liposomes to carry the prodrug to the tumor’s hypoxic regions. There, the lack of oxygen triggers its metabolic conversion to vinblastine.

In both formulations – one with polyethylene glycol on its surface, one without – the prodrug proved both safe and much more effective against non-small cell lung cancer than when it was delivered without a liposome.

“One of the hallmarks of these solid tumors is their hypoxic regions,” said the study’s lead author, Adam Alani of the OSU College of Pharmacy. “One reason these cancers become very aggressive is the development of this hypoxia. Since the late 1990s, researchers have been trying to take advantage of the hypoxia. The tumor model we chose, lung cancer, is one of the very well established tumors and there’s a very strong hypoxia associated with that – as well as, lung cancer is one of these cancers that in its advanced stages, it’s a terminal disease, and there’s a need for new treatments.”

By itself, vinblastine-N-oxide had shown less than optimal efficacy in testing by Cascade Prodrug because of how fast the body clears it from the system – it has a half-life of less than half an hour.

“When it was tested in mice and dogs, it did not have a chance to assimilate in the cancer tissue to produce the desired pharmacological effect,” Alani said.

But the liposomes – both the “pegylated” one containing polyethylene glycol, and the non-pegylated one – increased the half-life dramatically: to 9.5 and 5.5 hours, respectively.

“The nano carriers performed much better than the prodrug itself,” Alani said. “We were able to literally cure the tumor.”

Alani’s research began with laboratory cultures and progressed to safety and efficacy testing in animals.

“We made sure the nanostructure platform worked properly against lung cancer in vitro, then looked at the safety of the formulation in healthy mice and looked at the maximum tolerated dose – the biggest dose you can use without producing side effects,” Alani said. “Then we determined how long the nano carriers could keep the drug in the blood compared to the drug without the nanostructures.”

When those data were “very encouraging,” Alani’s team assessed the efficacy of the formulations in mice that had tumors grafted into them.

Without any liposome, the drug showed some tumor suppression, but the mice that had received the drug alone had to be euthanized after 70 days because of tumors that were no longer being controlled.

Mice that had received the drug with one of the liposomes were healthy and tumor-free for the nearly 100-day run of the experiment.

“The formulations clearly performed better than the unformulated drug as well as much better than Cisplatin, the standard-of-care drug for this research,” Alani said. “Now we’re collaborating with Cascade Prodrug and the College of Veterinary Medicine to assess safety and efficacy in dog models, and trying to look at other tumors, like bladder cancer, associated with dogs.”

One goal, Alani said, is to develop a new treatment for cancer in dogs, and another is to look at dogs as a model for drug development – “to get data Cascade can use to move the process forward for approval for use in dogs, as well as preliminary data for a new drug application with the FDA,” Alani said.

The Oregon Nanoscience and Microtechnologies Institute supported this research. Findings were recently published in the Journal of Controlled Release.

Co-authors on the paper were Alani’s colleagues in the Department of Pharmaceutical Sciences, Vidhi Shah, Duc Nguyen and Adel Alfatease, and Shay Bracha of the OSU veterinary college’s Department of Clinical Sciences.

About the OSU College of Pharmacy: The College of Pharmacy prepares students of today to be the pharmacy practitioners and pharmaceutical sciences researchers of tomorrow by contributing to improved health, advancing patient care and the discovery and understanding of medicines.

Cascade Prodrug Receives Gap Funds From ONAMI

EUGENE, Ore. – (November 7, 2014) – Cascade Prodrug, Inc. agreed to terms for funding from Oregon Nanoscience and Microtechnologies Institue, (ONAMI) in the budgeted amount of $250,000 for a development project to be conducted by Dr. Adam Alani, Assistant Professor, Oregon State University College of Pharmacy. The collaboration is focused on the development of a nanoparticle formulation for enhancing the pharmacokinetics of Hypoxia-Activated Prodrugs for treating ovarian cancer. “Dr. Alani brings deep experience in formulating drugs to our program and provides an exciting new dimension to Cascade’s prodrug technology platform,” stated August Sick, Cofounder and Managing Director.

Cascade Prodrug Closes Series A Financing

EUGENE, Ore. – (June 29, 2012) – Cascade Prodrug, Inc. closed on a preferred series A financing in excess of $1.4mm. The round was led by The Oregon Angel Fund. The proceeds will be used to further develop in preclinical trials the company’s novel prodrug technology platform for its lead compounds. “We are gratified by confidence shown by investors funding the further development of these exciting prodrugs,” commented Allan Cochrane, Cascade’s President and Cofounder.

Cascade Prodrug Awarded Federal Economic Stimulus Grant

EUGENE, Ore. – (October 29, 2010) – Cascade Prodrug, Inc. was awarded a Qualifying Therapeutic Discovery Grant in the amount of $244,479. “The grant will facilitate the preclinical development of our lead compound CPD100, a hypoxia-activated prodrug for the treatment of cancer,” said August Sick, Cascade’s Cofounder and Managing Director. Cascade Prodrug’s platform technology provides chemical conversion of approved chemotherapy drugs into potentially safer and more effective prodrugs for treating cancer.

Cascade ProDrug, University of Oregon acquire Novacea technology

Deal aims to create anti-cancer drugs that target oxygen-deprived tissues

EUGENE, Ore. — (Dec. 15, 2009) — Cascade ProDrug Inc. and the University of Oregon have completed an agreement that gives the company exclusive ownership of technology to make medicines that “turn on” in oxygen-starved tissues. The innovation could lead to improved treatments for cancer and other diseases marked by excessive cell growth.

Under the terms of the deal, Cascade ProDrug of Eugene becomes sole owner of a bundle of experimental compounds, technical data and patent rights that previously belonged to Novacea Inc., a publicly traded corporation that merged with Transcept Pharmaceuticals Inc. (NASDAQ: TSPT) in February 2009.

Novacea had generated the technology package — which focuses on a biochemical mechanism known technically as hypoxia activation — through years of research and development in collaboration with the laboratory of UO professor John Keana, a medicinal chemist who holds 70 U.S. patents and is one of Oregon’s most prolific inventors.

When Novacea decided in 2008 to change its research and development focus to other projects, the UO acquired the technology package to create the nucleus of a new Oregon company. The deal provides the UO with an equity stake in Cascade ProDrug, as well as royalties should patented products reach the marketplace. Cascade ProDrug also provided Transcept Pharmaceuticals a consideration package as part of the agreement.

Cascade ProDrug’s founders are serial entrepreneur Allan Cochrane and August Sick, former Life Technologies Corp. executive. “Cascade ProDrug is delighted to complete this transaction with the University of Oregon, and we’re eager to move forward with further development of this promising technology for hypoxia-activated medicines,” Cochrane said.

“The University of Oregon celebrates the birth of this latest spinout company from our institution’s research and industrial collaboration,” said Rich Linton, the university’s vice president for research and graduate studies. “This is yet another great example of how the university and its world-class research scientists are entrepreneurially engaging with the private sector to create exciting innovations with real potential to benefit Oregon and society.”

About Cascade ProDrug Inc.

Cascade ProDrug Inc. is a new drug discovery company developing targeted therapeutics against hyperproliferative diseases. The company’s initial focus is on anti-cancer medicines activated by tumor hypoxia. The platform technology acquired from the UO enables the company to reformulate existing chemotherapy agents with the potential to make them safer and more effective in treating solid tumors. The body of work already completed by Novacea and the UO provides Cascade ProDrug a head start on a series of lead compounds. Cascade ProDrug intends to contract research for final stages of preclinical trials and push toward the filing of an Investigational New Drug with the U.S. Food and Drug Administration.

About the University of Oregon

The University of Oregon is a world-class teaching and research institution and Oregon’s flagship public university. The UO is a member of the Association of American Universities (AAU), an organization made up of the 62 leading public and private research institutions in the United States and Canada. The University of Oregon is one of only two AAU members in the Pacific Northwest.

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