Comparison of paclitaxel penetration in normal and cancerous cervical model monolayer membranes A. Preetha a , N. Huilgol b , R. Banerjee a,∗ a School of Biosciences and Bioengineering, Indian Institute of Technology at Bombay, Mumbai 400076, India b Division of Radiation Oncology, Nanavati Hospital, Mumbai, India Abstract The aim of the present study was to evaluate the penetration of paclitaxel in normal as well as cancerous human cervical monolayer membranes and to compare these results with the paclitaxel penetration in a model dipalmitoylphosphatidylcholine (DPPC) monolayer. At physiologically relevant surface pressures of 30 mN/m, equilibrium drug penetration was observed in DPPC model membrane, whereas in cervical lipid model membranes exclusion of the drug and destabilization of the membrane was observed. The maximum surface pressure increment due to penetration (π max ) of 600 nM paclitaxel, for DPPC monolayer was found to be 3.6, 5.4 and 5.0 times higher than those for penetration in the cancerous monolayer at surface pressures 10, 20 and 30 mN/m, respectively. At initial surface pressure 10 mN/m, the maximum surface pressure increment, for 600 nM paclitaxel penetration, of normal cervical lipid membrane was double that of the cancerous cervical lipid membrane. At 30 mN/m initial surface pressure the representative IC 50 concentration of the drug produced negligible drug penetration and significant membrane destabilization in cervical lipid model membranes. The difference in penetration profile could be due to differences in composition of the model membranes. The cholesterol level in cancerous cervical membrane was 1.5-folds higher than that in the normal cervical membrane. Apart from PC, another constituent present in 20–32% in cancerous and normal membranes is sphingomyelin (SM). Introduction of 70% SM to the DPPC monolayer decreased the π max from 4.7 to 1.1 mN/m, revealing the rigidifying effect of SM which was directly proportional to the amount of SM added. Modulation of fluidity of the membranes can alter the penetration of paclitaxel in biological membranes and hence its toxicity profile. Keywords: Langmuir monolayer; Drug penetration; Cervical cancer; Surface pressure; Paclitaxel 1. Introduction The interaction between pharmacologically active com- pounds and the cell membrane plays a fundamental role in the pharmacokinetics of the drug [1]. The essential condition of attaining a therapeutic effect of the drug is its penetration to the site of action at a suitable concentration [2]. Most of the anticancer drugs are hydrophobic in nature and their efficacy is determined by their molecular interactions with lipid mem- branes in cancer cells [3]. Regardless of the mechanism for drug uptake, drugs must penetrate one or more membranes to exhibit biological activity. The main features of drug–membrane inter- actions in chemotherapy can be studied by using simple model systems [3]. The specific aspects of biological phenomena at the mem- brane level can be studied using suitable membrane models like lipid bilayers, lipid vesicles and lipid monolayers [4]. Though vesicles are simple to prepare and widely used as membrane models, the small radius of curvature may impose certain strong constraints at the polar head group of the phos- pholipids. On the other hand, lipid monolayer models using Langmuir films are simple membrane models for the investi- gation of drug–cell interactions which have several advantages. Monolayer models are known for their homogeneity, stabil- ity and planar geometry with specific orientations. Monolayers are bidimensional systems that can provide rigorous thermody- namic analysis. A number of parameters like nature and packing of lipid molecules, composition of the subphase, temperature can be selected without any limitation. Closer simulation of biological conditions is thus possible in such model systems by choosing the temperature and the appropriate subphase or monolayer composition.