Permeation thresholds for hydrophilic small biomolecules across microvascular and epithelial barriers are predictable on basis of conserved biophysical properties

Abstract

PurposeNeutral small hydrophiles are permeable to varying degrees, across the aqueous pores of phospholipid bilayer protein channels, with their potential for permeation into cells being predictable, on the basis of hydrophilicity and size. Here, it is hypothesized that permeation thresholds for small hydrophiles, across capillary zona occludens tight junction and inter-epithelial junction pore complexes are predictable, on the basis of predicted hydrophilicity in context of predicted molecular size and charge distribution, as are those of cations and anions, on the basis of predicted ionization in context of predicted atomic size.MethodsSmall hydrophiles are categorized by charge distribution. 2-dimensional plots of predicted hydrophilic octanol-to-water partition coefficient (HOWPC; unitless) and predicted van der Waals diameter (vdWD; nm) are generated for each category. The predicted HOWPC-to-vdWD ratio (nm-1), and vdWDs for permeable hydrophile at the maximum and minimum HOWPC-to-vdWD, vdWD @ MAXimum HOWPC-to-vdWD and vdWD @ MINimum HOWPC-to-vdWD are determined. For cations and anions, the ionization-to-atomic diameter ratios (CI or AI-to-AD ratios; nm-1) are determined.ResultsPer sizes of mixed and pure polyneutral hydrophiles, the permeation size maximum for hydrophiles across tight junction pore complexes is >0.69 ≤ 0.73 nanometers and across inter-epithelial junction pore complexes is ≥ 0.81 nanometers. For hydrophiles with anionicity or cationicity, the vdWDs @ MAXimum HOWPC-to-vdWD are less than those of mixed and polyneutral hydrophiles across both tight and inter-epithelial junctions, ranges specific to category and junction type. For cations, the permeation threshold across tight junctions is between the CI-to-AD ratio of Na+ (+2.69 nm-1) and CH3-Hg+ (+2.36 nm-1), with CH3-Hg+ and K+ (+2.20 nm-1) being permeable; and for divalent cations, the threshold across inter-epithelial junctions is between the CI-to-AD ratio of Mg2+ (+6.25 nm-1) and Ca2+ (+5.08 nm-1) , Ca2+ being semi-permeable. For anions, the permeation threshold across tight junctions is between the AI-to-AD ratio of Cl- (-4.91 nm-1) and Br- (-4.17 nm-1), and the threshold across inter-epithelial junctions is between the AI-to-AD ratio of F- (-7.81 nm-1) and Cl- (-4.91 nm-1).ConclusionsIn silico modeling reveals that permeation thresholds, of small molecule hydrophiles, cations and anions across junctional pore complexes, are conserved in the physiologic state.Electronic supplementary materialThe online version of this article (doi:10.1186/s40203-015-0009-y) contains supplementary material, which is available to authorized users.

Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

“…Thus, such xenobiotic chemotherapies have shown the potential to be uniformly cytotoxic to tumor cells, via effects in both nuclear and mitochondrial compartments in the setting of an actively maintained concentration gradient in vitro, particularly synergistically (28,29). Therefore, in order to demonstrate similar effectiveness in the clinical setting, such small molecule xenobiotics, as well as others discussed herein, must be made to first and foremost selectively accumulate to effective concentrations within tumor tissue, which can only be accomplished upon labile linking to optimally-sized, and designed, nanoparticles within the 8-to 9-nm-size range delivered transvascularly (3)(4)(5)(6)(7), to ensure uniform cytotoxicity to all tumor tissue cells and minimal risk for subsequent neoplastic transformation of tumor-associated cells including tumor stem cells.…”

“…This is the case of those within the overall lipophilicity range of cyclophosphamide/ifosfamide (Log OWPC-to-vdWD ratio, 0.14 nm -1 ; vdWD, 0.73 nm) (34,42,43) which are of larger size, and carmustine (Log OWPC-to-vdWD ratio, 1.41 nm -1 ; vdWD, 0.67 nm) (44), which is more lipophilic (44), for which there is a greater tendency to associate with and perturb CM phospholipids and the potential for a 1ary indirect pressuromodulation-mediated secondary increase in very high molecular weight (MW) protein transcription (17), while such small molecule xenobiotics of lipophilic character may only achieve intra-cellular levels at significant extracellular concentrations (45), which makes the more lipophilic xenobiotics of this category marginal chemoxenobiotics for effective transvascular delivery into solid tumor tissue (3)(4)(5)(6)(7) .…”

“…CM receptor growth factor or cytokine pressuromodulation/partial pressuromodulation antagonism-based synergistic approaches with the potential for tumorocidal tumorocytotoxicity include those employing ones such as staurosporine (59,164,167,168), imatinib (200), MK-2206 (201) and topotecan (186), particularly, upon effective transvascular delivery into solid tumors across VEGF-derived and maintained diaphragm fenestrated tumor blood capillaries (3)(4)(5)(6)(7)(8).…”

“…During the discovery and developmental stages, the testing of small molecule xenobiotics occurs at several levels: i) at the naked target, on chromatin or on a protein receptor/enzyme in isolation, which provides information on relative binding affinities for intra-cellular proteins; ii) at the cellular level in vitro, which provides information on the inhibitory concentrations needed to achieve tumor cell death and the overexpression status of induced pro-or anti-apoptotic protein forms, but does not take into consideration cell membrane (CM) phospholipid or CM protein receptor interactions, the most common level of interaction for secondary intra-cellular effects of non-permeable small molecule xenobiotics, either due to molecular size restriction to permeation or charge restriction to permeation (4,8); iii) at the systemic level in vivo, which gives an idea of the dosing range necessary to achieve a chemotherapeutic effect and tumor regression, and in the case of more lipophilic chemoxenobiotics, the dosing required to overcome serum protein binding, this being the primary limitation to achieving effective transvascular delivery and intra-tumoral concentrations in cases of free small molecule xenobiotics, not linked to optimally sized nanoparticles (3)(4)(5)(6)(7).…”

“…The insight to be gained is to be applicable for the selection of existing chemoxenobiotics most synergistic in cytotoxic effects and the development of more effective existing chemotherapy regimens utilizing small molecule chemoxenobiotics (14,15). This knowledge is applicable for the discovery of alternative xenobiotics with chemotherapeutic potential to overcome chemotherapeutic resistance (16), as well as for the design and development of next generation biocompatible optimally sized drug carriers free from intravascular protein interactions, for effective transvascular delivery into solid tumor tissue cells (3)(4)(5)(6)(7).…”