Nanoparticle-Encapsulated Leelamine Shown Safe for Treating Malignant Melanoma

Cancer researchers have packaged an effective but highly toxic cancer drug into a nano-liposome package that can be delivered to malignant melanoma cells with minimal damage to surrounding normal tissues.

The drug, leelamine, which is a natural compound isolated from pine bark, is a diterpene compound and a weak agonist of the cannabinoid CB1 receptor. Leelamine has been reported to inhibit PDK (pyruvate dehydrogenase kinase) activity.

The PI3 kinase (PI3K), MAP kinase (MAPK), and STAT3 molecular pathways promote disease development by being constitutively activated in 50%–70% of melanomas. In earlier studies leelamine inhibited the growth of preexisting xenografted melanoma tumors by an average of 60% by targeting the PI3K, MAPK, and STAT3 pathways without affecting animal body weight or blood markers of major organ function. The mechanism of action of leelamine was mediated by disruption of cholesterol transport, causing decreased cellular proliferation and, consequently leading to increased tumor cell apoptosis as well as decreased tumor vascularization.

Unfortunately, leelamine is not a suitable drug for use in humans due to its poor bioavailability and lethality when administered intravenously. To overcome these limitations, investigators at The Pennsylvania State University College of Medicine (Hershey, USA) developed a delivery system for leelamine based on nanoparticle-sized liposomes. The nano-liposomes (nicknamed Nanolipolee-007) could be loaded stably with leelamine up to 60% of their volume.

Results published in the October 2014 edition of the journal Molecular Cancer Therapeutics revealed that the Nanolipolee-007 nanoparticles were as effective at killing melanoma cells as leelamine dissolved in DMSO and were more effective at killing cultured melanoma compared with normal cells. Mechanistically, the Nanolipolee-007 particles acted in a fashion identical to natural leelamine by inhibiting PI3K/Akt, STAT3, and MAPK signaling mediated through inhibition of cholesterol transport.

Nanolipolee-007 inhibited the growth of preexisting xenografted melanoma tumors by an average of 64% by decreasing cellular proliferation, reducing tumor vascularization, and increasing cellular apoptosis, with negligible toxicity.

“The drug is packaged into a lipid ball significantly smaller than the width of a hair to make it soluble in the blood stream and prevent negative side effects. The drug-containing nanoparticle ball then travels in the bloodstream to the tumor, where it accumulates and the drug is released in the tumor to kill the cancer cells,” said senior author Dr. Gavin Robertson, professor of pharmacology, pathology, dermatology, and surgery at The Pennsylvania State University College of Medicine. “This nanoparticle moves leelamine one step closer to the clinic. We now have a drug that has the potential to be given to humans that could not be done before.”

Pennsylvania State University has patented this discovery and has licensed it to Melanovus Oncology (Jensen Beach, FL, USA) to conduct a series of FDA-required studies to enable clinical testing of the drug in humans.

Related Links:
The Pennsylvania State University College of Medicine
Melanovus Oncology