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Abstract

Summary Molecular charge is one of the main determinants of transvascular transport. There are, however, no data available on the effect of molecular charge on microvascular permeability of macromolecules in solid tumours. To this end, we measured tumour microvascular permeability to different proteins having similar size but different charge. Measurements were performed in the human colon adenocarcinoma LS174T transplanted in transparent dorsal skinfold chambers in severe combined immunodeficient (SCID) mice. Bovine serum albumin (BSA) and IgG were fluorescently labelled and were either cationized by conjugation with hexamethylenediamine or anionized by succinylation. The molecules were injected i.v. and the fluorescence in tumour tissue was quantified by intravital fluorescence microscopy. The fluorescence intensity and pharmacokinetic data were used to calculate the microvascular permeability. We found that tumour vascular permeability of cationized BSA (pI-range: 8.6-9.1) and IgG (pI: 8.6-9.3) was more than two-fold higher (4.25 and 4.65 × 10 -7 cm s -1 ) than that of the anionized BSA (pI ≈ 2.0) and IgG (pI: 3.0-3.9; 1.11 and 1.93 × 10 -7 cm s -1 , respectively). Our results indicate that positively charged molecules extravasate faster in solid tumours compared to the similar-sized compounds with neutral or negative charges. However, the plasma clearance of cationic molecules was ~2 × faster than that of anionic ones, indicating that the modification of proteins enhances drug delivery to normal organs as well. Therefore, caution should be exercised when such a strategy is used to improve drug and gene delivery to solid tumours.

Cancer nanotechnology: The impact of passive and active targeting in the era of modern cancer biology

“…When measuring the tumor uptake of a compound, the distinction between extravasated material in the vicinity of the vessels and the material which is taken up by tumor endothelial cells in the neovasculature is difficult. Some researchers describe enhanced interactions with endothelial cells, for example by cationic charges (see section1.3.2), as an increase in the effective P of the vessel [53, 54]; others consider these interactions to be the product of absorption and endocytosis by the endothelium [55, 56]. The black box accounts, among other things, for that uncertainty on the effective concentration in the vasculature available for extravasation ( i.e.…”

“…Once again, it is usually difficult to address both phenomenon independently [54]. The presence of surface charge can alter the opsonisation profile of the material, its recognition by cells in the organs of the MPS and its overall plasma circulation profile (↓ C v ) [11, 12, 86-92].…”

Strategies for advancing cancer nanomedicine

“…Cationic nanoparticles may penetrate tumours more than neutral or anionic particles 44 as a result of attractive electrostatic forces between cationic particles and anionic endothelial glycocalyx 45 . Yet neutral or anionic particles distribute throughout tumours more effectively than cationic particles 46 because of minimized binding to anionic matrix molecules 28 .…”

Design considerations for nanotherapeutics in oncology

“…Notice, that because these particles travel with the velocity of the fluid, some of them might not bind to the vessel wall and go through the wall openings into the tumor interstitial space. Indeed, experimental and theoretical studies have shown that cationic nanoparticles have superior transvascular flux compared to their anionic or neutral counterparts 69,74–78 . Furthermore, studies using zwitterionic quantum dot particles have shown that the spatial configuration of the surface charge plays also a role in the amount of the particles that crosses the vessel wall 79 .…”