Optical Imaging Visualizes a Homogeneous and Horizontal Band-Like Biodistribution of Large- and Small-Size Hydrophilic Compounds Delivered by Ablative Fractional Laser

Abstract

The skin barrier generally limits the topical delivery of hydrophilic molecules. Ablative fractional laser (AFL) facilitates cutaneous drug uptake of smaller hydrophilic compounds in several studies. In this imaging-based study, we aim to investigate the cutaneous biodistribution of two different-sized hydrophilic compounds delivered by an ablative fractional CO2 laser at minimally invasive settings. Intact or CO2 AFL-pretreated (2.5 mJ/mb and 5% density) ex vivo porcine skin was topically applied with a large or small hydrophilic compound (fluorescence labeled antibody nivolumab (150,000 g/mol, n = 4) or ATTO 647N (746 g/mol, n = 3)). Samples were incubated for 20 h in a Franz cell setup, whereafter optical coherence tomography (OCT) was used to assess laser channel depth, and ex vivo confocal microscopy (EVCM) was used to assess epidermal thickness and cutaneous biodistribution of nivolumab and ATTO 647N. With an EVCM-assessed median epidermal thickness of 70.3 µm and OCT-assessed ablation depth of 31.9 µm, minimally invasive settings enabled shallow penetration into the mid-epidermis. The AFL-assisted uptake of the antibody nivolumab and the smaller compound ATTO 647N showed a similar homogenous and horizontal band-like biodistribution pattern that reached mid-dermis. No uptake of nivolumab or ATTO 647N was observed in intact skin. In conclusion, AFL-induced mid-epidermal laser channels facilitates the cutaneous delivery of two hydrophilic compounds that are distributed in a similar homogeneous and horizontal band-like pattern, irrespective of their molecular size.

Laser‐assisted topical delivery of vismodegib reduces hedgehog gene expression in human basal cell carcinomas in vivo

“…Future studies would further benefit from establishing intratumoral spatial biodistribution of vismodegib as laser-assisted drug delivery tends to yield the highest concentrations closest to the skin surface. 20,21,24,30 Routinely reported in pharmacokinetic studies, plasma concentrations have served as a proxy for vismodegib tissue deposition 4,25,26 but the relationship between plasma and tumor tissue concentrations has not previously been substantiated. Our preliminary data suggests that concentrations in plasma and BCCs are comparable after systemic vismodegib, which may establish plasma concentrations as a viable surrogate for intratumoral vismodegib accumulation.…”

“…Accordingly, additional studies are required to determine the frequency of vismodegib reapplication needed to support the continuous presence of intratumoral vismodegib. Future studies would further benefit from establishing intratumoral spatial biodistribution of vismodegib as laser‐assisted drug delivery tends to yield the highest concentrations closest to the skin surface 20,21,24,30 …”

“…14 Ablative fractional laser (AFL) has been widely shown in preclinical and clinical studies to enhance the uptake of topically applied drugs by providing a grid of microchannels that facilitate drug diffusion across the skin barrier. [15][16][17] The concept may also be used to provide topical delivery of drugs that are otherwise delivered systemically, [18][19][20][21][22][23] which has also been demonstrated in a clinical setting for BCC treatment. 24 We have previously described AFL-assisted topical delivery of a vismodegib emulsion in preclinical studies, which led to high cutaneous vismodegib concentrations in healthy porcine skin.…”