Page 44 - IJB-9-6

International Journal of Bioprinting Transdermal delivery of printed cisplatin

cancer is attracting great interest in these studies. In this are sufficient to achieve strong response in HR-deficient
regard, tumors with mutations in KMT2C, which encodes lung tumors when the treatment is combined with oral
a histone modifier with a rather indirect role in HR repair, administration of the olaparib. The proposed approach
emerge as a promising stratification marker for identifying alleviates the cytotoxic side effects of the combination
patients who could benefit from PARPi. Together with therapy while eliminating the need for intravenous
identifying tumors with somatic mutations in HR-related administration of cisplatin in the hospital.
genes and/or proven HR deficiency through molecular
analysis or functional assays, this collection of diagnostic Acknowledgments
techniques can very likely identify patients who comprise
a significant portion of the total lung cancer cases. None.
Since PARPi interfere with DNA damage repair, Funding
combination with other DNA-damaging agents such as
cisplatin could be advantageous. Clinical practice, however, This work has been co-financed by the European Union and
has indicated that combination of PARPi and cisplatin at Greek national funds through the Operational Program
the respective standard monotherapy dose is intolerable Competitiveness, Entrepreneurship, and Innovation, under
due to toxicity. Their combination, however, at lower dose the call RESEARCH–CREATE–INNOVATE (project code:
seems to lead to clinical benefit in HR-deficient tumors . T1EDK-00976). G.A.S. acknowledges funding from the
[12]
Cisplatin intercalates into DNA generating intrastrand European Research Council (ERC) under the European
and interstrand adducts that, if not resolved, physically Union’s Horizon 2020 research and innovation program
obstruct DNA polymerases during DNA replication, (ERC Grant agreement no. 758705).
leading to the generation of double-strand breaks .
[57]
Cisplatin could remain in the human body, and traces of Conflict of interest
it can be found in the urine of patients even after 8 years The authors declare no conflict of interest.
from the treatment . We thus hypothesize that because
[58]
of its high potency and long excretion kinetics, even low Author contributions
levels of cisplatin could lead to increased DNA damage.
Because PARPi is efficacious already as monotherapy in Conceptualization: Zoi Kanaki, Constantin Tamvakopoulos,
HR-deficient tumors, we hypothesize that even low levels Ioanna Zergioti, Apostolos Klinakis
of cisplatin are sufficient to sensitize cells to PARPi and Formal analysis: Zoi Kanaki, Alexandra Smina, Chrysoula
maximize synthetic lethality. Chandrinou, Ilias Cheliotis, Georgios A. Sotiriou,
Apostolos Klinakis
To eliminate the need for hospital visit for intravenous Investigation: Zoi Kanaki, Chrysoula Chandrinou, Fotini E.
administration of cisplatin, we have developed transdermal Koukouzeli, Yiannis Ntounias, Nikolaos Paschalidis,
MNs which have been coated with cisplatin through LIFT Marina Makrygianni, Jill Ziesmer, Constantin
technology. Cisplatin can be readily detectable in the blood Tamvakopoulos, Apostolos Klinakis
stream and also in the tumors in mouse models of non- Methodology: Zoi Kanaki, Alexandra Smina, Chrysoula
small cell lung cancer. Although these levels are lower than Chandrinou, Fotini E. Koukouzeli, Yiannis Ntounias,
those achieved through intraperitoneal administration, the Nikolaos Paschalidis, Ilias Cheliotis, Jill Ziesmer,
two approaches have comparable efficacy when combined Georgios A. Sotiriou, Ioanna Zergioti, Constantin
with oral olaparib. The obvious advantage of transdermal Tamvakopoulos, Apostolos Klinakis
administration of cisplatin without the need for hospital Writing – original draft: Zoi Kanaki, Alexandra Smina,
visits, as well as the ability to precisely adjust the dose with Chrysoula Chandrinou, Nikolaos Paschalidis,
the use of LIFT technology, offers an attractive approach Jill Ziesmer, Georgios A. Sotiriou, Constantin
for combination therapies with cisplatin. Tamvakopoulos, Ioanna Zergioti, Apostolos Klinakis
Writing – review & editing: Zoi Kanaki, Alexandra Smina,
5. Conclusion Chrysoula Chandrinou, Nikolaos Paschalidis,
Jill Ziesmer, Georgios A. Sotiriou, Constantin
This work demonstrates for the first time that cisplatin Tamvakopoulos, Ioanna Zergioti, Apostolos Klinakis
printed onto MNs can be used for transdermal
administration in mouse models of cancer. Transdermally- Ethics approval and consent to participate
administered cisplatin reaches the bloodstream as well
as the tumor itself, and although drug levels are lower All procedures for care and treatment of animals were
than those obtained with intraperitoneal injection, they approved by the Institutional Committee on Ethics of

Volume 9 Issue 6 (2023) 36 https://doi.org/10.36922/ijb.0048