Interaction of Camptothecin with Model Cellular Membranes

Abstract

Accurate and efficient prediction of drug partitioning in model membranes is of significant interest to the pharmaceutical industry. Herein, we utilize advanced sampling methods, specifically, the adaptive biasing force methodology to calculate the potential of mean force for a model hydrophobic anticancer drug, camptothecin (CPT), across three model interfaces. We consider an octanol bilayer, a thick octanol/water interface, and a model 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/water interface. We characterize the enthalpic and entropic contributions of the drug to the potential of mean force. We show that the rotational entropy of the drug is inversely related to the probability of hydrogen bond formation of the drug with the POPC membrane. In addition, in long-time microsecond simulations of a high concentration of CPT above the POPC membrane, we show that strong drug–drug aromatic interactions shift the spatial orientation of the drug with the membrane. Stacks of hydrophobic drugs form, allowing penetration of the drug just under the POPC head groups. These results imply that inhomogeneous membrane models need to take into account the effect of drug aggregation on the membrane environment.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Tamoxifen [204], Cytarabine [205], 5-Fluorouracil [206,207], Daunorubicin [208,209], β-Lapachone [210], Minerval [211], Miltefosine [212], Tofacitinib [213], Edelfosine [214], Miltefosine [214], Perifosine [214], Camptothecin [215,216], Pirarubicin, Ellipticine [217], Perillyl alcohol [218], Cisplatin [219,220], Doxorubicin [179,217,221], 5-fluorouracil [206];…”

The interaction of supramolecular anticancer drug amphiphiles with phospholipid membranes

“…We hypothesize that there are competing free energy contributions between the inter-and intra-nanocluster interactions. In other words, the enthalpic interactions between the POPC and the 'qCPT-buSS-Tau' nanoclusters, specically the camptothecin, 43 are more favorable than the mainly hydrophobic and stacking interactions that hold the 'qCPT-buSS-Tau' nanoclusters together. As a result, the POPC membrane allows the 'qCPT-buSS-Tau' nanoclusters inside, leading via the hydrophobic CPT, breaking the larger aggregates.…”

“…38 Nonetheless, conventional MD simulations cannot take into account the reversible dynamics of the disulde bonds. CPT is a model hydrophobic anticancer drug 41 with a known octanol/water partition coefficient 42,43 that can p-p stack in solution due to its planar aromatic structure, 44 driving the self-assembly process. Dependent on the molecular structure of the DAs, such as the number of conjugated drugs ('mCPT' or 'mCPT-buSS-Tau', which has one drug attached, vs. 'qCPT' or 'qCPT-buSS-Tau', which has four drugs attached), the shape of the selfassembly in solution ranges from nanolament (diameter $ 6.5 nm) to nanotube (diameter $ 9.5 nm).…”

A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues

“…D values were calculated based on both absorbance or fluorescence nonlinear fittings and used to express membrane distribution of CPT as log D values (Table 2). DMPC or DMPG [16,49] Fluorescence anisotropy 2.00 ± 0.16 *** DOPC [50] 1.55 ± 0.05 *** DOPG [50] 1.97 ± 0.05 *** Octanol: water [18,50,51] Fluorescence When the logD values for the membrane models and pH values mimetic of normal and cancer cells are compared, regardless of the method used (derivative UV-Vis spectroscopy or fluorescence spectroscopy), it can be concluded that CPT can distribute between the membrane and aqueous phases with no significant differences, with an average logD value of 2.89 ± 0.23, which is typical of intermediate to lipophilic molecules (0< logD < 3) [29]. A drug's ability to distribute between membrane/aqueous media indicates that it can penetrate cell membranes through the phospholipid polar head region, diffuse through lipophilic hydrocarbon chains, and emerge into the inner region of phospholipid polar headgroups, which determines its body distribution [52,53].…”

“…The lipophilicity of drugs is typically expressed as a partition of the drug in the octanol/water system, and the reported logP value (value of drug distribution at a pH value where the drug is in its neutral form) of CPT in the octanol/water system was 1.73 ± 0.08 [18,50,51] (Table 2), whereas the in silico calculated logD (at pH 7.4 or 5.8) and logP values in the octanol/water system using Chemaxon ® software was 1.52 (Table 1), i.e. significantly lower than the distribution logD values determined in vitro in the membrane/aqueous system (Table 2).…”