An orally bioavailable nanoformulation of betulinic acid, for melanoma

Melanoma is cancer that impacts 69,000 Americans each year, killing approximately 7,000 of them annually. Melanoma cases have doubled over the last three decades, and with the increased popularity of tanning bed usage (an activity which has been reported to increase melanoma risk by 70%), the number of cases is expected to soar. Melanoma is a deadly disease in dire need of a medical solution.

Betulinic Acid – A Unique Melanoma-Specific Natural Product

We are developing a natural drug, betulinic acid, that is found in the bark of the widely available white birch tree. This drug is very specific for killing melanoma cancer cells with no measurable toxicity to normal cells.

Betulinic acid has demonstrated cytotoxic activity specific for melanoma cells both in vitro and in vivo. In vitro, this melanoma-specific cytotoxicity occurs through apoptosis; however, this mechanism is not well understood. When administered intraperitoneally (i.p.) to athymic mice bearing human melanoma xenografts, betulinic acid is concentrated in the tumors, resulting in rapid tumor regression with no observable toxicity to the animal even at high doses (e.g., 500 mg/Kg body weight, i.p.). Direct injection of betulinic acid into the tumor of xenografts induced apoptosis within the tumors.

Poor Water Solubility Limiting Full Therapeutic Efficacy

Unfortunately, betulinic acid is quite insoluble; this insolubility has hampered its clinical development and commercial use. Betulinic acid, a potential clinical candidate that came through NCI’s RAID mechanism, was abandoned because of lack of oral bioavailability. It was meant for chronic dosing and no viable, nontoxic, IV formulation could be developed.

Several water-soluble and prodrug derivatives have been made in recent years, with the most famous being Bevirimat, 3-O-(3′,3′-dimethylsuccinyl)-betulinic acid (PA-457). Unfortunately, this efficacy has not yet translated in vivo in the clinic. While some of the variability in clinical results has been correlated with patients’ genetic makeup, some of the difficulties have been associated with making the active site of betulinic acid orally bioavailable. The active site of the molecule is the carboxylic acid group since this is the only difference between betulinic acid and its precursor betulin, which is totally inactive.

APH-0201 – Improved Betulinic Acid Drug Delivery and Bioavailability

APH-0201 is betulinic acid nanoparticles in biodegradable polymer nanospheres that will allow transport to the stomach and enhance oral bioavailability.

Betulinic acid, a pentacyclic triterpene, and its precursor, betulinare components of the bark of the Betula alba (white birch) tree. The tree is fast-growing and abundant in North America and Europe.

Betulinic acid is manufactured from the bark of this tree by Aphios using our supercritical fluid extraction and chromatography CXP enabling technology platform.

Betulinic acid nanoparticles are first formed using PNP technology and then encapsulated into biodegradable polymer nanospheres using PNS technology to form APH-0201.

APH-0201 drug nanoparticles can be taken as pills, improving the drug’s ability to reach the melanoma cancer cells and reducing hospitalization time and costs.

APH-0201 Benefits and Advantages

• This is a new paradigm for the treatment of melanoma cancer, which is still a significant unmet medical need.
• By providing chemotherapeutics orally, it may be possible to treat cancer as a chronic disease, rather than a recurring acute disease, and afford long-term solutions for disease suppression and patient care.
• With an oral delivery option, it will be possible to administer lower doses of the chemotherapeutic agent over an extended period of time.
• APH-0201 will reduce or eliminate the need for protracted intravenous delivery of drugs, benefitting patients in terms of convenience.
• This drug will shrink the overall costs of evaluation/treatment by reducing or eliminating hospitalization and/or visits to clinics.