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Laser printing of Gemcitabine on microneedles
demonstrated the successful delivery of Gem in the release profile with smaller Gem dosages loaded onto
bloodstream for all tested doses. A comparison of MN MNs and further investigations are underway to explore
transdermal application and intraperitoneal injection of this possibility. Based on our findings in this study, we
0.1 mg of Gem in mice revealed that the transdermal believe that MN dosing is a viable alternative to the
approach produced similar results but at a slower release oral dose. Future studies should include more extended
rate than the IP. It should be noted that the short half- pharmacokinetic protocols as well as their applicability
life of Gem through IP administration as demonstrated by to the preclinical efficacy models to further explore the
previous reports led to the design of this study protocol benefits of the described approach.
[33]
by selecting the specific time points. This was also shown
in our results (Figure 9). However, our results show that Acknowledgments
the MN approach after 1 h is beneficial, and this will be This research has been co-financed by the European Union
investigated further. and Greek national funds through the Operational Program
Although significant Gem concentrations (low μM) Competitiveness, Entrepreneurship and Innovation,
were achieved in mouse plasma at the lower Gem dose under the call RESEARCH–CREATE–INNOVATE
(100 μg), such concentrations are not expected to lead to (project code: T1EDK-00976). G.A.S. acknowledges
toxicity as compared with other administration routes of funding from the European Research Council (ERC)
chemotherapeutics Thus, in comparison with other dosing under the European Union’s Horizon 2020 research and
routes (IP or intravenous dosing), the MNs described here innovation program (ERC Grant agreement n° 758705).
could be an ideal tool for metronomic dosing strategies.
The benefits of metronomic dosing can only be achieved Part of Figure 8A has been created using Biorender.com
with appropriate dosing choices (e.g., oral) since drug Conflict of interest
administration has to be performed frequently.
The doses tested in this study were those that could The authors have no conflict of interest to declare.
be achieved (100 – 750 μg in one MN patch) based on
drug solubility in the appropriate vehicle. Dosing in Author contributions
mice ranged from 5 – 37.5 mg/kg (the average weight I.Z., A.K. and C.T. conceived the idea for the project. Z.K.
of mice in the study was 20 g). In order to determine developed the animal models and performed the animal
clinical relevance, Gem is dosed in humans as follows: dosing experiments and contributed to the writing of the
1000 – 1250 mg/m (approximately 30 – 37.5 mg/kg) as manuscript. C.C. performed the LIFT high-speed camera
2
a standard dose of intravenous infusion once a week for experiments for the coating of the MNs, contributed to the
3 – 4 weeks. Alternative dosing schemes for metronomic LIFT experiments for the coating of the MNs, analyzed
therapy include a more frequent schedule of every 3 day the LIFT process data, and also contributed to the writing
rd
with a low-dose infusion of 250 mg/m 7.5 mg/kg) of the manuscript. I-M.O developed and performed
2 (
Gem . Clinical studies of the oral availability of Gem the HPLC-MS/MS quantification methodology and
[39]
have found very low systemic exposure due to rapid the pharmacokinetics analysis and contributed to the
first-pass metabolism to dFdU (doses up to 8 mg, or writing of the manuscript. C.K. contributed to the LIFT
0.12 mg/kg), suggesting that only a pro-drug approach experiments for the coating of the MNs. J.Z. performed
could be used to provide metronomic Gem with the MN fabrication and contributed in writing - editing.
appreciable concentrations following oral dosing [33,40] .
G.A.S. supervised the MN fabrication experiments,
5. Conclusions analyzed data and contributed to the writing-editing of
the manuscript.
This work presents a novel approach to coat MN patches
in ambient conditions using the LIFT technique. The References
LIFT process successfully coated PPMA MNs with (i) 88
μg, (ii) 388 μg, and (iii) 1019 μg of Gem for transdermal 1. Waghule T, Singhvi G, Dubey SK, et al., 2019, Microneedles:
application in mice, in a reliable and reproducible manner. A Smart Approach and Increasing Potential for Transdermal
Application of MNs with the three aforementioned Drug Delivery System. Biomed Pharmacother, 109:1249–58.
amounts of Gem in mice led to blood Gem concentrations https://doi.org/10.1016/j.biopha.2018.10.078
averaging 479, 1353, and 3067 ng/mL respectively, at 2. Sirbubalo M, Tucak A, Muhamedagic K, et al., 2021,
15 min and increased considerably after 1h, suggesting 3D Printing a “Touch-Button” Approach to Manufacture
that administration of Gem through MNs can lead to
prolonged systemic exposure. Furthermore, a comparative Microneedles for Transdermal Drug Delivery. Pharmaceutics,
study between transdermal delivery and IP injection 13:924.
was performed and the results suggested a sustained https://doi.org/10.3390/pharmaceutics13070924

144 International Journal of Bioprinting (2022)–Volume 8, Issue 3