The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers

Abstract

Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications and can be found in household items, including foods, cosmetics, and cleaning supplies. Over the past three decades, it has also been investigated for its potential anticancer activity. Clinical trials with an oral POH formulation administered to cancer patients failed to realize therapeutic expectations, although an intra-nasal POH formulation yielded encouraging results in malignant glioma patients. Based on its amphipathic nature, POH revealed the ability to overcome biological barriers, primarily the blood–brain barrier (BBB), but also the cytoplasmic membrane and the skin, which appear to be characteristics that critically contribute to POH’s value for drug development and delivery. In this review, we present the physicochemical properties of POH that underlie its ability to overcome the obstacles placed by different types of biological barriers and consequently shape its multifaceted promise for cancer therapy and applications in drug development. We summarized and appraised the great variety of preclinical and clinical studies that investigated the use of POH for intranasal delivery and nose-to-brain drug transport, its intra-arterial delivery for BBB opening, and its permeation-enhancing function in hybrid molecules, where POH is combined with or conjugated to other therapeutic pharmacologic agents, yielding new chemical entities with novel mechanisms of action and applications.

Intranasal Delivery of miR133b in a NEO100-Based Formulation Induces a Healing Response in Spinal Cord-Injured Mice

“…Perillyl alcohol (POH) is a naturally occurring monoterpene, a non-nutritive dietary constituent found in essential oils of citrus fruits, peppermint, spearmint, cherries, and herbs with antioxidant, anti-inflammatory and anti-tumor activities [ 11 , 12 ]. Scientific studies demonstrated its beneficial role as a neuroprotector against ischemia-reperfusion injury in a middle cerebral artery occlusion (MCA) model of stroke in rats [ 13 ] and against amyloid beta (Aß)- neurotoxicity in a cellular model of Alzheimer’s disease in SY5Y neuroblastoma cells [ 14 ].…”

From the groin to the brain: a transfemoral path to blood-brain barrier opening

“…NEO100 (NeOnc Technologies, Inc., Los Angeles, CA, USA) is an ultra-pure, pharmaceutical-grade version of perillyl alcohol, a naturally occurring monoterpenoid that is present, for example, in the essential oils of citrus fruit peel as a metabolite of limonene. Like perillyl alcohol [ 13 ], NEO100 has been extensively investigated for its cancer therapeutic potential, and recently published results from a Phase 1 trial applying intranasal delivery of NEO100 to recurrent glioblastoma patients showed exceptional safety and encouraging signs of activity [ 14 , 15 ]. Independent from these intranasal studies that focused on NEO100’s potential as a cancer therapeutic, Wang et al pursued the question whether IA injection of NEO100 would result in BBB opening in a manner that is safe and reversible, and potentially useful to enable beneficial brain entry of otherwise low-BBB-permeable therapeutics, such as methotrexate and therapeutic antibodies.…”

Isothermal Vapor–Liquid Equilibrium Data for a Binary System of (−)-α-Pinene + (−)-Limonene and a Quaternary System of (−)-α-Pinene + (−)-Limonene + Water + Ethephon at 313.2, 323.2, and 333.2 K

“…17,18 (−)-Limonene, a component of turpentine, is widely used in food, pharmaceuticals, cosmetics, etc. 19 It has anti-inflammatory, 20 antidiabetic, 21 antioxidant, 22 and anti-cancer 23 activities in medicine and has positive effects in the treatment of gastric ulcers 24 and asthma. 25 Limonene can also be used as mercury absorbers by forming polymers with sulfur.…”