Topical Delivery of Nivolumab, a Therapeutic Antibody, by Fractional Laser and Pneumatic Injection.
Identifieur interne : 000014 ( Main/Exploration ); précédent : 000013; suivant : 000015Topical Delivery of Nivolumab, a Therapeutic Antibody, by Fractional Laser and Pneumatic Injection.
Auteurs : Rikke L. Christensen [Danemark] ; Silje H. Omland [Danemark] ; Daniel P. Persson [Danemark] ; S Ren Husted [Danemark] ; Merete Haedersdal [Danemark] ; Uffe H. Olesen [Danemark]Source :
- Lasers in surgery and medicine [ 1096-9101 ] ; 2020.
Abstract
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 CO
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/cm
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.
DOI: 10.1002/lsm.23322
PubMed: 32997833
Affiliations:
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Omland</name><affiliation wicri:level="1"><nlm:affiliation>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400, Denmark.</nlm:affiliation><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400</wicri:regionArea><wicri:noRegion>2400</wicri:noRegion></affiliation></author><author><name sortKey="Persson, Daniel P" sort="Persson, Daniel P" uniqKey="Persson D" first="Daniel P" last="Persson">Daniel P. 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Olesen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400, Denmark.</nlm:affiliation><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400</wicri:regionArea><wicri:noRegion>2400</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32997833</idno><idno type="pmid">32997833</idno><idno type="doi">10.1002/lsm.23322</idno><idno type="wicri:Area/Main/Corpus">000041</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000041</idno><idno type="wicri:Area/Main/Curation">000041</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000041</idno><idno type="wicri:Area/Main/Exploration">000041</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Topical Delivery of Nivolumab, a Therapeutic Antibody, by Fractional Laser and Pneumatic Injection.</title><author><name sortKey="Christensen, Rikke L" sort="Christensen, Rikke L" uniqKey="Christensen R" first="Rikke L" last="Christensen">Rikke L. Christensen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400, Denmark.</nlm:affiliation><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400</wicri:regionArea><wicri:noRegion>2400</wicri:noRegion></affiliation></author><author><name sortKey="Omland, Silje H" sort="Omland, Silje H" uniqKey="Omland S" first="Silje H" last="Omland">Silje H. Omland</name><affiliation wicri:level="1"><nlm:affiliation>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400, Denmark.</nlm:affiliation><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400</wicri:regionArea><wicri:noRegion>2400</wicri:noRegion></affiliation></author><author><name sortKey="Persson, Daniel P" sort="Persson, Daniel P" uniqKey="Persson D" first="Daniel P" last="Persson">Daniel P. Persson</name><affiliation wicri:level="1"><nlm:affiliation>Department of Plant and Environmental Sciences, Faculty of Science, University of Copenhagen, Frederiksberg, 1870, Denmark.</nlm:affiliation><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Plant and Environmental Sciences, Faculty of Science, University of Copenhagen, Frederiksberg, 1870</wicri:regionArea><wicri:noRegion>1870</wicri:noRegion></affiliation></author><author><name sortKey="Husted, S Ren" sort="Husted, S Ren" uniqKey="Husted S" first="S Ren" last="Husted">S Ren Husted</name><affiliation wicri:level="1"><nlm:affiliation>Department of Plant and Environmental Sciences, Faculty of Science, University of Copenhagen, Frederiksberg, 1870, Denmark.</nlm:affiliation><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Plant and Environmental Sciences, Faculty of Science, University of Copenhagen, Frederiksberg, 1870</wicri:regionArea><wicri:noRegion>1870</wicri:noRegion></affiliation></author><author><name sortKey="Haedersdal, Merete" sort="Haedersdal, Merete" uniqKey="Haedersdal M" first="Merete" last="Haedersdal">Merete Haedersdal</name><affiliation wicri:level="1"><nlm:affiliation>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400, Denmark.</nlm:affiliation><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400</wicri:regionArea><wicri:noRegion>2400</wicri:noRegion></affiliation></author><author><name sortKey="Olesen, Uffe H" sort="Olesen, Uffe H" uniqKey="Olesen U" first="Uffe H" last="Olesen">Uffe H. Olesen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400, Denmark.</nlm:affiliation><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400</wicri:regionArea><wicri:noRegion>2400</wicri:noRegion></affiliation></author></analytic><series><title level="j">Lasers in surgery and medicine</title><idno type="eISSN">1096-9101</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><b>BACKGROUND AND OBJECTIVES</b></p><p>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).</p></div><div type="abstract" xml:lang="en"><p><b>STUDY DESIGN/MATERIALS AND METHODS</b></p><p>In vitro porcine skin was exposed to CO</p></div><div type="abstract" xml:lang="en"><p><b>RESULTS</b></p><p>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/cm</p></div><div type="abstract" xml:lang="en"><p><b>CONCLUSIONS</b></p><p>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.</p></div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">32997833</PMID><DateRevised><Year>2020</Year><Month>09</Month><Day>30</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1096-9101</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2020</Year><Month>Sep</Month><Day>30</Day></PubDate></JournalIssue><Title>Lasers in surgery and medicine</Title><ISOAbbreviation>Lasers Surg Med</ISOAbbreviation></Journal><ArticleTitle>Topical Delivery of Nivolumab, a Therapeutic Antibody, by Fractional Laser and Pneumatic Injection.</ArticleTitle><ELocationID EIdType="doi" ValidYN="Y">10.1002/lsm.23322</ELocationID><Abstract><AbstractText Label="BACKGROUND AND OBJECTIVES" NlmCategory="OBJECTIVE">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).</AbstractText><AbstractText Label="STUDY DESIGN/MATERIALS AND METHODS" NlmCategory="METHODS">In vitro porcine skin was exposed to CO<sub>2</sub> 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.</AbstractText><AbstractText Label="RESULTS" NlmCategory="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/cm<sup>3</sup> (100 µm), 105.8 µg/cm<sup>3</sup> (500 µm), and 19.3 µg/cm<sup>3</sup> (1500 µm), corresponding to 2-10% of the applied concentration, with the highest deposition in the mid dermis. Immediate EPI delivered 429.4 µg/cm<sup>3</sup> (100 µm), 584.9 µg/cm<sup>3</sup> (500 µm), and 295.9 µg/cm<sup>3</sup> (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.</AbstractText><AbstractText Label="CONCLUSIONS" NlmCategory="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.</AbstractText><CopyrightInformation>© 2020 Wiley Periodicals LLC.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Christensen</LastName><ForeName>Rikke L</ForeName><Initials>RL</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-0806-5621</Identifier><AffiliationInfo><Affiliation>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400, Denmark.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Omland</LastName><ForeName>Silje H</ForeName><Initials>SH</Initials><Identifier Source="ORCID">https://orcid.org/0000-0001-7611-5208</Identifier><AffiliationInfo><Affiliation>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400, Denmark.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Persson</LastName><ForeName>Daniel P</ForeName><Initials>DP</Initials><Identifier Source="ORCID">https://orcid.org/0000-0003-3976-190X</Identifier><AffiliationInfo><Affiliation>Department of Plant and Environmental Sciences, Faculty of Science, University of Copenhagen, Frederiksberg, 1870, Denmark.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Husted</LastName><ForeName>Søren</ForeName><Initials>S</Initials><Identifier Source="ORCID">https://orcid.org/0000-0003-2020-1902</Identifier><AffiliationInfo><Affiliation>Department of Plant and Environmental Sciences, Faculty of Science, University of Copenhagen, Frederiksberg, 1870, Denmark.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Haedersdal</LastName><ForeName>Merete</ForeName><Initials>M</Initials><Identifier Source="ORCID">https://orcid.org/0000-0003-1250-2035</Identifier><AffiliationInfo><Affiliation>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400, Denmark.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Olesen</LastName><ForeName>Uffe H</ForeName><Initials>UH</Initials><Identifier Source="ORCID">https://orcid.org/0000-0002-4578-684X</Identifier><AffiliationInfo><Affiliation>Department of Dermatology and Wound Healing Centre, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, 2400, Denmark.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><Agency>Greater Copenhagen Health Science Partners</Agency><Country></Country></Grant><Grant><GrantID>0052695</GrantID><Agency>Fabrikant Vilhem Pedersen og Hustrus Legat on the recommendation of The Novo Nordisk Foundation</Agency><Country></Country></Grant><Grant><GrantID>LF18045</GrantID><Agency>LEO Fondet</Agency><Country></Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>09</Month><Day>30</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Lasers Surg Med</MedlineTA><NlmUniqueID>8007168</NlmUniqueID><ISSNLinking>0196-8092</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">PD-1 inhibitor</Keyword><Keyword MajorTopicYN="N">ablative fractional laser</Keyword><Keyword MajorTopicYN="N">biodistribution</Keyword><Keyword MajorTopicYN="N">dermatology</Keyword><Keyword MajorTopicYN="N">drug delivery</Keyword><Keyword MajorTopicYN="N">electronically controlled pneumatic injection</Keyword><Keyword MajorTopicYN="N">laser ablation-inductively coupled plasma-mass spectrometry</Keyword><Keyword MajorTopicYN="N">needle-free injection</Keyword><Keyword MajorTopicYN="N">nivolumab</Keyword><Keyword MajorTopicYN="N">skin cancer</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>07</Month><Day>07</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2020</Year><Month>08</Month><Day>27</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>09</Month><Day>09</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>9</Month><Day>30</Day><Hour>17</Hour><Minute>13</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>10</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>10</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>aheadofprint</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32997833</ArticleId><ArticleId IdType="doi">10.1002/lsm.23322</ArticleId></ArticleIdList><ReferenceList><Title>REFERENCES</Title><Reference><Citation>Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. 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Sci Rep 2017;7(1):12751.</Citation></Reference></ReferenceList></PubmedData></pubmed><affiliations><list><country><li>Danemark</li></country></list><tree><country name="Danemark"><noRegion><name sortKey="Christensen, Rikke L" sort="Christensen, Rikke L" uniqKey="Christensen R" first="Rikke L" last="Christensen">Rikke L. Christensen</name></noRegion><name sortKey="Haedersdal, Merete" sort="Haedersdal, Merete" uniqKey="Haedersdal M" first="Merete" last="Haedersdal">Merete Haedersdal</name><name sortKey="Husted, S Ren" sort="Husted, S Ren" uniqKey="Husted S" first="S Ren" last="Husted">S Ren Husted</name><name sortKey="Olesen, Uffe H" sort="Olesen, Uffe H" uniqKey="Olesen U" first="Uffe H" last="Olesen">Uffe H. Olesen</name><name sortKey="Omland, Silje H" sort="Omland, Silje H" uniqKey="Omland S" first="Silje H" last="Omland">Silje H. Omland</name><name sortKey="Persson, Daniel P" sort="Persson, Daniel P" uniqKey="Persson D" first="Daniel P" last="Persson">Daniel P. 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