Going Pro?

debut their new technology for preparing and using proliposomal nanoemulsions of ropivacaine in both piglet and human subjects exposed to painful stimuli. Nano is an expression adopted from the Greek word “νᾶνος” meaning “dwarf” and was approved in 1960 as an International Systems of Units prefix to mean a 10−9 (i.e., billionth) scale descriptor for base units describing mass, time, length, and others. With further specification, nanotechnology was coined by Taniguchi in 1974 to explicitly name the length scalar to denote nanometer dimensions of materials and “. mainly consists of the processing of separation, consolidation and deformation of materials by one atom or one molecule. ”3 At these sizes, quantum effects become important, and these materials may display seemingly bizarre behavior unfamiliar to us living at the full-meter scale. For example, gold nanoparticles may visually appear crimson in color because of electron confinement and melt at only 300°C (in contrast, a gold bar melts at approximately >1000°C). Thaxton et al.4 used some unique properties of nanogold to develop a “. gold nanoparticle bio-barcode assay probe for the detection of prostate-specific antigen at 330 femtograms/mL. ” A femtogram is 10−15 g. Indeed, nanotechnology has grown in every sector of the economy with health care functions now coming into development. In anesthesiology, nanotechnology has been reported primarily related to the areas of drug delivery (e.g., propofol, local anesthetics, volatile anesthetics). 5–9 The present articles on proliposomal emulsions go further to articulate the use of nanotechnology in medicine.1,2 Liposomes are one type of nanotechnology, with the word simply meaning “fat body. ” This class was created in the 1960s with a central compartment surrounded by a spherical shell-like assembly of surfactants (e.g., phospholipids) with nanometer-to-micrometer diameters. For years, scientists have inserted a variety of drugs (especially hydrophobic medications) into the central compartment in hopes of using liposomes as a drug delivery vehicle. Indeed, the very first report (identified by the present author) of local anesthetics bound within liposomes for anesthesia was reported in Anesthesia & Analgesia in 1988 by Gesztes and Mezei,10 wherein tetracaine was encapsulated in liposomes to provide effective topical anesthesia. Nearly 3 decades later, the potential for deposition of local anesthetic-loaded liposomes is still recognized although only 1 product (ExparelTM; Pacira Pharmaceuticals, Inc., San Diego, CA) is available currently in the United States and then it is only approved for surgical site infiltration, whereas central and regional anesthesia is not recommended.11 Why? The reasons are clear and not new. Others have previously editorialized to wonder whether liposomal formulations are safe for perineural injection.12,13 For example, what are the effects, if any, of injection of 1, 2-dierucoylphosphatidylcholine, 8.2 mg/mL (an inactive ingredient of Exparel), or other surfactants in close proximity to the brachial plexus for a large population (e.g., 100,000) of patients? Until safety issues can be definitively addressed, enthusiasm for liposome-based bupivacaine and other nanotechnology will be markedly diminished. Also, liposome manufacturing is not as highly developed as it is for single-molecule formulations (e.g., conventional bupivacaine). Indeed, it can be difficult to achieve the high degree of chemistry, manufacturing, and control between batches the public expects of US Food and Drug Administration-approved products. Finally, our only experience using liposomal bupivacaine for femoral nerve block resulted in unexpected, “. biologically implausible. ” results, wherein the magnitude of femoral nerve block was inversely related to the bupivacaine dose.14 Bizarre behavior indeed. Clearly, more work needs to be done to understand the effects of local anesthetics bound in liposomes on peripheral nerves. Moreover, this proliposomal technology is so novel that one must first think about the evolving definition of a prodrug. In referencing “pro” in the name of a pharmaceutical, one may think of prodrugs that are already routinely used in modern medicine such as clopidogrel, fospropofol, and others. From this perspective, a classic prodrug does not possess any intrinsic pharmacologic activity but instead serves as a substrate for the endogenous metabolism to produce a metabolite that causes a pharmacologic effect. The proliposomal emulsions described in the accompanying articles are not the type of classic prodrug you studied in medical school. Instead, in recent years, a number of “prodrugs” have been developed that attach an active drug to a carrier moiety of some type. These pharmaceuticals are now also called prodrugs, although this new designation adds confusion about the traditional definition of a prodrug. Going Pro?