Fundamentals of fractional laser-assisted drug delivery: An in-depth guide to experimental methodology and data interpretation

Wenande, Emily; Anderson, R. R.; Hædersdal, Merete

doi:10.1016/j.addr.2019.10.003

Cited by 67 publications

(97 citation statements)

References 120 publications

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“…Alternatively, AFL‐induced oozing and vasodilation could have altered the drug's delivery and removal. This phenomenon would present a problem for agents that require extended exposure durations to exert their effect, and may partly explain why some topical therapies do not achieve the expected boost in efficacy when combined with AFL delivery [17].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Laser‐Assisted Combination Chemotherapy: An Explorative Imaging‐Guided Treatment With 5‐Fluorouracil and Cisplatin for Basal Cell Carcinoma

et al. 2020

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Background and Objectives Rising incidences of basal cell carcinoma (BCC) have increased the need for effective topical therapies. By enhancing cutaneous uptake of the chemotherapeutic agents, cisplatin and 5‐fluorouracil (5‐FU), laser‐assisted delivery may provide a new combination treatment for BCC. Accordingly, this study aimed to evaluate tumor response, safety, and drug biodistribution in tumors and blood after topical laser‐assisted 5‐FU + CIS treatment in BCC patients. Study Design/Materials and Methods This open‐label, proof‐of‐concept trial investigated laser‐assisted combination cisplatin + 5‐FU treatment in 20 patients with histologically verified, low‐risk superficial or nodular BCCs on the face (<20 mm) or trunk/extremities (<50 mm). After tumor demarcation guided by optical coherence tomography (OCT), BCCs were exposed to ablative fractional CO2 laser followed by 60 minutes topical cisplatin solution and 7‐day exposure to 5% 5‐FU cream under occlusion. After 30 days, treatment was repeated if any tumor residual was identified. Tumor response at day 30 and month 3 was assessed clinically as well as by OCT, reflectance confocal microscopy, and ultrasound, supplemented by histological verification at 3 months. Local skin reactions (LSRs) and side effects were evaluated on days 1, 3–5, 14, 30, and month 3. Drug detection in tumors and blood was performed in a subset of patients 1‐ and 24 hours after treatment. Results Nineteen patients completed the trial, with 32% (6/19) receiving a single treatment and 68% (13/19) treated twice. At 3 months, clinical clearance was seen in 18/19 patients with a corresponding 94% (17/18) achieving histological clearance. Baseline tumor thickness and subtype did not influence treatment number or clearance rate (P ≥ 0.61). LSRs were well‐tolerated and consisted of erythema, edema, and erosion, followed by crusting by day 14. Erythema declined gradually by month 3, with 94% of patients and 79% of physicians rating cosmesis as “good” or “excellent.” Scarring or hyperpigmentation was noted in 50% and 56%, respectively, while pain and infection were not observed during the follow‐up period. Although chemotherapy uptake was visualized extending to deep skin layers, no systemic exposure to cisplatin or 5‐FU was detected in patient blood. Conclusion Laser‐assisted cisplatin + 5‐FU shows potential as an effective and tolerable treatment option for low‐risk BCC, particularly in instances where self‐application is not possible or where in‐office, non‐surgical therapy is preferred. Lasers Surg. Med. © 2020 Wiley Periodicals LLC

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Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Laser‐Assisted Combination Chemotherapy: An Explorative Imaging‐Guided Treatment With 5‐Fluorouracil and Cisplatin for Basal Cell Carcinoma

et al. 2020

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“…To overcome these restraints, other physical delivery techniques have been developed to provide effective intradermal drug delivery [2]. These techniques include laser-assisted drug delivery, microneedling, electrochemotherapy, iontophoresis, and jet injectors [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Electronic Pneumatic Injection‐Assisted Dermal Drug Delivery Visualized by Ex Vivo Confocal Microscopy

et al. 2020

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Background and Objectives: Electronic pneumatic injection (EPI) is a technique for dermal drug delivery, which is increasingly being used in clinical practice. However, only few studies have been reported on cutaneous drug distribution and related clinical endpoints. We aimed to visualize the immediate cutaneous drug distribution, changes in skin architecture, and related clinical endpoint of EPI. Study Design/Materials and Methods: Acridine orange (AO) solution was administered to ex vivo porcine skin by EPI at pressure levels from 4 to 6 bar with a fixed injection volume of 50 µl and nozzle size of 200 µm. Immediate cutaneous distribution was visualized using ex vivo confocal microscopy (EVCM). Changes in skin architecture were visualized using both EVCM and hematoxylin and eosin-stained cryosections. Results: The defined immediate endpoint was a clinically visible papule formation on the skin. The pressure threshold to consistently induce a papule was 4 bar, achieving delivery of AO to the deep dermis (2319 µm axial and 5944 µm lateral distribution). Increasing the pressure level to 6 bar did not lead to significant differences in axial and lateral dispersion (P = 0.842, P = 0.905; respectively). A distinctively hemispherical distribution pattern was identified. Disruption of skin architecture occurred independently of pressure level, and consisted of subepidermal clefts, dermal vacuoles, and fragmented collagen. Conclusions: This is the first study to relate a reproducible clinical endpoint to EPI-assisted immediate drug delivery using EVCM. An EPI-induced skin papule indicates dermal drug delivery throughout all layers of the dermis, independent of pressure level settings. Lasers Surg. Med.

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“…However, the stability of the lanthanide complex should be confirmed in future studies by extracting and characterizing the complex at the end of the study. Finally, in our study, we used porcine skin, which resembles human skin better than mouse skin, which was used in previous studies, investigating AFL-assisted delivery of antibodies [11,38].…”

Section: Discussionmentioning

confidence: 99%

“…Energy-based devices may serve as a modality to deliver drugs that are otherwise unable to cross the skin barrier. Laser-assisted drug delivery (LADD) using an ablative fractional laser (AFL) is a well-described energy-based method to improve topical dermatological treatments for skin diseases [10,11]. By passive diffusion through fractionally ablated channels, drugs permeate skin layers with minimal systemic absorption, thereby reducing systemic side effects.…”

Section: Introductionmentioning

confidence: 99%

“…LADD has facilitated topical drug uptake of multiple smaller anticancer agents such as 5-fluorouracil (130 Da) [12], cisplatin (300 Da) [13], vismodegib (431 Da) [14], methotrexate (455 Da) [15], and bleomycin (1415 Da) [16]. Unassisted drug penetration through the stratum corneum is primarily dependent on the molecular weight and water solubility of the drug, where large and hydrophilic drugs show negligible permeability [11,17]. Although nivolumab is a large hydrophilic molecule-approximately 100 times larger than bleomycin-molecules of similar molecular weight such as botulinum toxin A [18] and anti-CD29 antibodies [19] have been delivered through laser-processed skin.…”

Section: Introductionmentioning

confidence: 99%

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Topical Delivery of Nivolumab, a Therapeutic Antibody, by Fractional Laser and Pneumatic Injection

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Background and Objectives PD‐L1 is a tumor ligand that binds to the PD‐1 receptor on immune cells, thereby inhibiting the antitumor immune response. The antibody nivolumab is a PD‐1 inhibitor, Food and Drug Administration approved for systemic treatment of several aggressive cancer types. Topically applied nivolumab may hold potential as a future strategy to treat keratinocyte cancer, but its molecular properties preclude unassisted topical uptake. The aim of this study was to investigate uptake and biodistribution of topically delivered nivolumab, assisted by two physical enhancement techniques with different delivery kinetics; ablative fractional laser (AFL) and electronically controlled pneumatic injection (EPI). Study Design/Materials and Methods In vitro porcine skin was exposed to CO2 AFL (20 mJ/mb, 5% density), followed by passive diffusion of nivolumab in a Franz cell (1 mg/ml, 18 hours, n = 6) or treated with EPI (4 bar) for immediate delivery of nivolumab (1 mg/ml, 10 minutes, n = 6). The resulting nivolumab skin concentrations were quantified by enzyme‐linked immunosorbent assay (ELISA) at three skin depths (100, 500, and 1500 µm), comparing the uptake from assisted delivery with intact skin. Biodistribution of nivolumab in the skin for all interventions was visualized by laser ablation‐inductively coupled plasma‐mass spectrometry (LA‐ICP‐MS) and fluorescence microscopy. Results Delivery of nivolumab by AFL‐assisted passive diffusion and immediate EPI both resulted in significantly enhanced uptake of nivolumab in all skin depths compared with intact skin (P < 0.05). With AFL, nivolumab concentrations reached 86.3 µg/cm3 (100 µm), 105.8 µg/cm3 (500 µm), and 19.3 µg/cm3 (1500 µm), corresponding to 2–10% of the applied concentration, with the highest deposition in the mid dermis. Immediate EPI delivered 429.4 µg/cm3 (100 µm), 584.9 µg/cm3 (500 µm), and 295.9 µg/cm3 (1500 µm) into the skin, corresponding to 29–58% of the applied nivolumab concentration. From qualitative visualization of the biodistribution, it appeared that nivolumab distributed in a horizontal and continuous homogenous band in the upper and mid dermis through AFL‐exposed skin, whereas EPI‐delivery showed a deep focal deposition extending into the deep dermis. Conclusions AFL‐assisted passive diffusion and immediate EPI‐assisted delivery show the potential to deliver therapeutic antibodies locally. Future in vivo and pharmacokinetic studies would reveal the full potential for topical antibody delivery by energy‐based devices. Lasers Surg. Med. © 2020 Wiley Periodicals LLC

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Fundamentals of fractional laser-assisted drug delivery: An in-depth guide to experimental methodology and data interpretation

Cited by 67 publications

References 120 publications

Efficacy and Safety of Laser‐Assisted Combination Chemotherapy: An Explorative Imaging‐Guided Treatment With 5‐Fluorouracil and Cisplatin for Basal Cell Carcinoma

Efficacy and Safety of Laser‐Assisted Combination Chemotherapy: An Explorative Imaging‐Guided Treatment With 5‐Fluorouracil and Cisplatin for Basal Cell Carcinoma

Electronic Pneumatic Injection‐Assisted Dermal Drug Delivery Visualized by Ex Vivo Confocal Microscopy

Topical Delivery of Nivolumab, a Therapeutic Antibody, by Fractional Laser and Pneumatic Injection

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