Laser-assisted delivery of synergistic combination chemotherapy in in vivo skin

Emily Wenande; Joshua Tam; Brijesh Bhayana; Steven Kyle Schlosser; Emily Ishak; William A Farinelli; Agata Chlopik; Mai P Hoang; Omar R Pinkhasov; Peter Caravan; R Rox Anderson; Merete Hædersdal

doi:10.1016/j.jconrel.2018.02.019

Laser-assisted delivery of synergistic combination chemotherapy in in vivo skin

Emily Wenande, Joshua Tam, Brijesh Bhayana, Steven Kyle Schlosser, Emily Ishak, William A Farinelli, Agata Chlopik, Mai P Hoang, Omar R Pinkhasov, Peter Caravan, R Rox Anderson, Merete Hædersdal

Department of Clinical Medicine

13 Citations (Scopus)

Abstract

The effectiveness of topical drugs for treatment of non-melanoma skin cancer is greatly reduced by insufficient penetration to deep skin layers. Ablative fractional lasers (AFLs) are known to enhance topical drug uptake by generating narrow microchannels through the skin, but information on AFL-drug delivery in in vivo conditions is limited. In this study, we examined pharmacokinetics, biodistribution and toxicity of two synergistic chemotherapy agents, cisplatin and 5-fluorouracil (5-FU), following AFL-assisted delivery alone or in combination in in vivo porcine skin. Detected at 0-120 h using mass spectrometry techniques, we demonstrated that fractional CO2 laser pretreatment (196 microchannels/cm2, 852 μm ablation depth) leads to rapid drug uptake in 1500 μm deep skin layers, with a sixfold enhancement in peak cisplatin concentrations versus non-laser-treated controls (5 h, P = 0.005). Similarly, maximum 5-FU deposition was measured within an hour of AFL-delivery, and exceeded peak deposition in non-laser-exposed skin that had undergone topical drug exposure for 5 days. Overall, this accelerated and deeper cutaneous drug uptake resulted in significantly increased inflammatory and histopathological effects. Based on clinical scores and transepidermal water loss measurement, AFL intensified local toxic responses to drugs delivered alone and in combination, while systemic drug exposure remained undetectable. Quantitative histopathologic analyses correspondingly revealed significantly reduced epidermal proliferation and greater cellular apoptosis after AFL-drug delivery; particularly after combined cisplatin + 5-FU exposure. In sum, by overcoming the primary limitation of topical drug penetration and providing accelerated, enhanced and deeper delivery, AFL-assisted combination chemotherapy may represent a promising treatment strategy for non-melanoma skin cancer.

Original language	English
Journal	Journal of Controlled Release
Volume	275
Pages (from-to)	242-253
Number of pages	12
ISSN	0168-3659
DOIs	https://doi.org/10.1016/j.jconrel.2018.02.019
Publication status	Published - 10 Apr 2018

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10.1016/j.jconrel.2018.02.019

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@article{c619d8c9f109415687903b8fa431c9c9,

title = "Laser-assisted delivery of synergistic combination chemotherapy in in vivo skin",

abstract = "The effectiveness of topical drugs for treatment of non-melanoma skin cancer is greatly reduced by insufficient penetration to deep skin layers. Ablative fractional lasers (AFLs) are known to enhance topical drug uptake by generating narrow microchannels through the skin, but information on AFL-drug delivery in in vivo conditions is limited. In this study, we examined pharmacokinetics, biodistribution and toxicity of two synergistic chemotherapy agents, cisplatin and 5-fluorouracil (5-FU), following AFL-assisted delivery alone or in combination in in vivo porcine skin. Detected at 0-120 h using mass spectrometry techniques, we demonstrated that fractional CO2 laser pretreatment (196 microchannels/cm2, 852 μm ablation depth) leads to rapid drug uptake in 1500 μm deep skin layers, with a sixfold enhancement in peak cisplatin concentrations versus non-laser-treated controls (5 h, P = 0.005). Similarly, maximum 5-FU deposition was measured within an hour of AFL-delivery, and exceeded peak deposition in non-laser-exposed skin that had undergone topical drug exposure for 5 days. Overall, this accelerated and deeper cutaneous drug uptake resulted in significantly increased inflammatory and histopathological effects. Based on clinical scores and transepidermal water loss measurement, AFL intensified local toxic responses to drugs delivered alone and in combination, while systemic drug exposure remained undetectable. Quantitative histopathologic analyses correspondingly revealed significantly reduced epidermal proliferation and greater cellular apoptosis after AFL-drug delivery; particularly after combined cisplatin + 5-FU exposure. In sum, by overcoming the primary limitation of topical drug penetration and providing accelerated, enhanced and deeper delivery, AFL-assisted combination chemotherapy may represent a promising treatment strategy for non-melanoma skin cancer.",

author = "Emily Wenande and Joshua Tam and Brijesh Bhayana and Schlosser, {Steven Kyle} and Emily Ishak and Farinelli, {William A} and Agata Chlopik and Hoang, {Mai P} and Pinkhasov, {Omar R} and Peter Caravan and {Rox Anderson}, R and Merete H{\ae}dersdal",

year = "2018",

month = apr,

day = "10",

doi = "10.1016/j.jconrel.2018.02.019",

language = "English",

volume = "275",

pages = "242--253",

journal = "Journal of Controlled Release",

issn = "0168-3659",

publisher = "Elsevier",

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TY - JOUR

T1 - Laser-assisted delivery of synergistic combination chemotherapy in in vivo skin

AU - Wenande, Emily

AU - Tam, Joshua

AU - Bhayana, Brijesh

AU - Schlosser, Steven Kyle

AU - Ishak, Emily

AU - Farinelli, William A

AU - Chlopik, Agata

AU - Hoang, Mai P

AU - Pinkhasov, Omar R

AU - Caravan, Peter

AU - Rox Anderson, R

AU - Hædersdal, Merete

PY - 2018/4/10

Y1 - 2018/4/10

N2 - The effectiveness of topical drugs for treatment of non-melanoma skin cancer is greatly reduced by insufficient penetration to deep skin layers. Ablative fractional lasers (AFLs) are known to enhance topical drug uptake by generating narrow microchannels through the skin, but information on AFL-drug delivery in in vivo conditions is limited. In this study, we examined pharmacokinetics, biodistribution and toxicity of two synergistic chemotherapy agents, cisplatin and 5-fluorouracil (5-FU), following AFL-assisted delivery alone or in combination in in vivo porcine skin. Detected at 0-120 h using mass spectrometry techniques, we demonstrated that fractional CO2 laser pretreatment (196 microchannels/cm2, 852 μm ablation depth) leads to rapid drug uptake in 1500 μm deep skin layers, with a sixfold enhancement in peak cisplatin concentrations versus non-laser-treated controls (5 h, P = 0.005). Similarly, maximum 5-FU deposition was measured within an hour of AFL-delivery, and exceeded peak deposition in non-laser-exposed skin that had undergone topical drug exposure for 5 days. Overall, this accelerated and deeper cutaneous drug uptake resulted in significantly increased inflammatory and histopathological effects. Based on clinical scores and transepidermal water loss measurement, AFL intensified local toxic responses to drugs delivered alone and in combination, while systemic drug exposure remained undetectable. Quantitative histopathologic analyses correspondingly revealed significantly reduced epidermal proliferation and greater cellular apoptosis after AFL-drug delivery; particularly after combined cisplatin + 5-FU exposure. In sum, by overcoming the primary limitation of topical drug penetration and providing accelerated, enhanced and deeper delivery, AFL-assisted combination chemotherapy may represent a promising treatment strategy for non-melanoma skin cancer.

AB - The effectiveness of topical drugs for treatment of non-melanoma skin cancer is greatly reduced by insufficient penetration to deep skin layers. Ablative fractional lasers (AFLs) are known to enhance topical drug uptake by generating narrow microchannels through the skin, but information on AFL-drug delivery in in vivo conditions is limited. In this study, we examined pharmacokinetics, biodistribution and toxicity of two synergistic chemotherapy agents, cisplatin and 5-fluorouracil (5-FU), following AFL-assisted delivery alone or in combination in in vivo porcine skin. Detected at 0-120 h using mass spectrometry techniques, we demonstrated that fractional CO2 laser pretreatment (196 microchannels/cm2, 852 μm ablation depth) leads to rapid drug uptake in 1500 μm deep skin layers, with a sixfold enhancement in peak cisplatin concentrations versus non-laser-treated controls (5 h, P = 0.005). Similarly, maximum 5-FU deposition was measured within an hour of AFL-delivery, and exceeded peak deposition in non-laser-exposed skin that had undergone topical drug exposure for 5 days. Overall, this accelerated and deeper cutaneous drug uptake resulted in significantly increased inflammatory and histopathological effects. Based on clinical scores and transepidermal water loss measurement, AFL intensified local toxic responses to drugs delivered alone and in combination, while systemic drug exposure remained undetectable. Quantitative histopathologic analyses correspondingly revealed significantly reduced epidermal proliferation and greater cellular apoptosis after AFL-drug delivery; particularly after combined cisplatin + 5-FU exposure. In sum, by overcoming the primary limitation of topical drug penetration and providing accelerated, enhanced and deeper delivery, AFL-assisted combination chemotherapy may represent a promising treatment strategy for non-melanoma skin cancer.

U2 - 10.1016/j.jconrel.2018.02.019

DO - 10.1016/j.jconrel.2018.02.019

M3 - Journal article

C2 - 29454062

SN - 0168-3659

VL - 275

SP - 242

EP - 253

JO - Journal of Controlled Release

JF - Journal of Controlled Release

ER -

Laser-assisted delivery of synergistic combination chemotherapy in in vivo skin

Abstract

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