Chemical penetration enhancers (CPEs) are present in a large number of transdermal, dermatological, and cosmetic products to aid dermal absorption of curatives and aesthetics. This wide spectrum of use is based on only a handful of molecules, the majority of which belong to three to four typical chemical functionalities, sporadically introduced as CPEs in the last 50 years. Using >100 CPEs representing several chemical functionalities, we report on the fundamental mechanisms that determine the barrier disruption potential of CPEs and skin safety in their presence. Fourier transform infrared spectroscopy studies revealed that regardless of their chemical make-up, CPEs perturb the skin barrier via extraction or fluidization of lipid bilayers. Irritation response of CPEs, on the other hand, correlated with the denaturation of stratum corneum proteins, making it feasible to use protein conformation changes to map CPE safety in vitro. Most interestingly, the understanding of underlying molecular forces responsible for CPE safety and potency reveals inherent constraints that limit CPE performance. Reengineering this knowledge back into molecular structure, we designed >300 potential CPEs. These molecules were screened in silico and subsequently tested in vitro for molecular delivery. These molecules significantly broaden the repertoire of CPEs that can aid the design of optimized transdermal, dermatological, and cosmetic formulations in the future. stratum corneum ͉ spectroscopy ͉ skin irritation ͉ lipid C urrently, hypodermic needles are the only available mode for systemic delivery of macromolecular drugs into humans. Transdermal delivery offers an attractive alternative to needlebased drug administration. However, evolved to impede the flux of exogenous molecules, stratum corneum (SC), the topmost layer of the skin, provides a strong barrier to molecular delivery. This is especially problematic for relatively large drugs (molecular mass Ͼ 500 Da), which represent a large majority of active agents for therapeutic applications (1). Over 350 molecules, termed chemical penetration enhancers (CPEs), have been identified to perturb the SC barrier to facilitate molecular delivery. However, incorporation of CPEs into products has been mitigated by safety concerns related to the health of the skin membrane (2-4). Accordingly, overcoming the skin barrier in a safe and effective way still remains the bottleneck of transdermal and topical therapies.Identification of chemicals to increase skin permeability has been an area of high activity in the last three decades (5-7). After an initial rise in the number of CPEs in the 1980s, the active pool of CPEs has reached a plateau in the last decade. In an era where new chemical entities are being discovered at an exponential rate (as indicated by the entries in the Chemical Abstract Service), the plateau in the number of CPE molecules is rather surprising (only 1 in 100,000 known molecules represents a CPE). This anomaly originates from the slow rates of syntheses of CPEs when compar...

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Although transdermal drug delivery is more attractive than injection, it has not been applied to macromolecules because of low skin permeability. Here we describe particular mixtures of penetration enhancers that increase skin permeability to macromolecules (approximately 1-10 kDa) by up to approximately 100-fold without inducing skin irritation. The discovery of these mixtures was enabled by an experimental tool, in vitro skin impedance guided high-throughput (INSIGHT) screening, which is >100-fold more efficient than current tools. In vitro experiments demonstrated that the mixtures delivered macromolecular drugs, including heparin, leutinizing hormone releasing hormone (LHRH) and oligonucleotides, across the skin. In vivo experiments on hairless rats with leuprolide acetate confirmed the potency and safety of one such mixture, sodium laureth sulfate (SLA) and phenyl piperazine (PP). These studies show the feasibility of using penetration enhancers for systemic delivery of macromolecules from a transdermal patch.

Carboxylated carbon nanotubes stand as the most promising nanovectors for biomedical and pharmaceutical applications due to their ease of covalent conjugation with eclectic functional molecules including therapeutic drugs, proteins, and oligonucleotides. In the present study, we attempt to investigate how the toxicity of acid-oxidized multiwalled carbon nanotubes (MWCNTs) can be tweaked by altering their degree of functionalization and correlate the toxicity trend with their biodistribution profile. In line with that rationale, mice were exposed to 10 mg/kg of pristine (p) and acid-oxidized (f) MWCNTs with varying degrees of carboxylation through a single dose of intravenous injection. Thereafter, extensive toxicity studies were carried out to comprehend the short-term (7 day) and long-term (28 day) impact of p- and various f-MWCNT preparations on the physiology of healthy mice. Pristine MWCNTs with a high aspect ratio, surface hydrophobicity, and metallic impurities were found to induce significant hepatotoxicity and oxidative damage in mice, albeit the damage was recovered after 28 days of treatment. Conversely, acid-oxidized carboxylated CNTs with shorter lengths, hydrophilic surfaces, and high aqueous dispersibility proved to be less toxic and more biocompatible than their pristine counterparts. A thorough scrutiny of various biochemical parameters, inflammation indexes, and histopathological examination of liver indicated that toxicity of MWCNTs systematically decreased with the increased functionalization density. The degree of shortening and functionalization achieved by refluxing p-MWCNTs with strong mineral acids for 4 h were sufficient to render the CNTs completely hydrophilic and biocompatible, while inducing minimal hepatic accumulation and inflammation. Quantitative biodistribution studies in mice, intravenously injected with Tc-99m labeled MWCNTs, clearly designated that clearance of CNTs from reticuloendothelial system (RES) organs such as liver, spleen, and lungs was critically functionalization density dependent. Well-individualized MWCNTs with shorter lengths (<500 nm) and higher degrees of oxidation (surface carboxyl density >3 μmol/mg) were not retained in any of the RES organs and rapidly cleared out from the systematic circulation through renal excretion route without inducing any obvious nephrotoxicity. As both p- and f-MWCNT-treated groups were devoid of any obvious nephrotoxicity, CNTs with larger dimensions and lower degrees of functionalization, which fail to clear out from the body via renal excretion route, were thought to be excreted via biliary pathway in faeces.

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