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International Journal of Bioprinting Transdermal delivery of printed cisplatin

clinical use . Among those, small molecules targeting is taken orally. Thus, alternative administration routes for
[2]
poly (ADP-ribose) polymerase (PARP1/2) became the cisplatin would be beneficial.
first drug designed to exploit synthetic lethality, a genetic Microneedles (MNs) have emerged as an alternative
concept described in model organism almost a century approach for transdermal drug delivery because they allow
ago . PARP1/2 proteins play an important role in the transdermal administration, reduced pain, and delivery of
[3]
repair of single-strand breaks of the DNA . molecules of high molecular weight. Drug-coated MNs,
[4]
An initial observation that cells carrying inactivating which are suitable for both hydrophilic and hydrophobic
mutations in the BRCA1 or BRCA2 genes cannot survive drugs [17-19] , are ideal for low-dose administration of
PARP inhibition [5,6] catalyzed efforts to therapeutically chemotherapeutic drugs, such as cisplatin [20-22] . This
target PARP proteins in cancer. Because women with approach would eliminate the need to visit the hospital for
germline mutations in these genes are at risk of developing intravenous administration of the drug. However, limited
breast and ovarian cancer, the first of a series of approvals drug quantity and drug material waste, as well as uniformity
by the U.S. Food and Drug Administration (FDA) for of coating, are major limitations of this approach.
PARP1/2 inhibitors (PARPi) came in 2014 for the small
molecule olaparib against ovarian cancer in patients Recently, three-dimensional (3D) printing technologies
[7]
carrying BRCA1 and BRCA2 mutations. These mutations have emerged as a valuable tool in the biomedical field. These
disrupt a DNA repair pathway known as homologous technologies allow for the layer-by-layer construction of
recombination (HR) repair, which is used to repair double- 3D structures using a variety of materials. The 3D printing
strand breaks . PARP inhibition leads to unrepaired approaches can be utilized to coat MNs by transporting
[8]
single-strand breaks, which in turn produce double-strand little microdroplets of the active pharmaceutical ingredient
breaks, which cannot be repaired by HR-deficient cells, (API) solution onto the MNs, hence creating uniform
such as those carrying inactivating mutations in BRCA1 layers. Inkjet printing has been successfully used for MN
[23-25]
and BRCA2. Eventually, these cells accumulate intolerable coating for transdermal delivery of anti-cancer drugs ;
levels of DNA damage and are driven to cell death. however, limitations with the deposition of highly viscous
inks onto a given substrate are encountered, and nozzle
Besides the development of multiple PARPi which clogging is observed [26,27] . Laser-induced forward transfer
are approved for several indications as monotherapy , (LIFT) , on the other hand, offers superior resolution,
[9]
[28]
multiple studies have focused on the combination of nozzle-free, and viscosity-independent laser printing of
PARPi with chemotherapy or other targeted therapies [10,11] . organic and inorganic material. We have previously used the
As serious dose-limiting toxicities were observed, a new LIFT technology to coat MNs with the chemotherapeutic
trial (clinicaltrials.gov identifier: NCT00782574) aimed drug gemcitabine. Transdermal application of the MNs in
to establish the maximum tolerable dose and to evaluate animal models leads to drug release, achieving substantial
the pharmacokinetics and preliminary efficacy of olaparib plasma levels .
[29]
in combination with cisplatin in patients with advanced
solid tumors. This study indicated that systematic Here, we exploited LIFT to coat MNs for transdermal
administration of olaparib orally (100 mg or 200 mg delivery of cisplatin in mice. Pharmacokinetic studies
twice a day) in combination with a standard single dose of indicated that transdermal application of the MNs
cisplatin (75 mg/m ) in the beginning of each 21-day cycle produced cisplatin plasma levels that were low but
2
was not tolerable . Some of the observed toxicities have detectable particularly at the later time points of the study
[12]
been previously described in olaparib clinical trials, while (24 h). We generated mouse xenograft models using HR-
others are clearly associated with cisplatin. Intermittent deficient non-small cell lung cancer cells, and, by exploiting
administration of olaparib at a lower dose (50 mg twice a synthetic lethality, we showed that transdermal delivery
day), which is close to the minimum dose of 60 mg twice of cisplatin in combination with oral olaparib leads to
daily that achieves 90% PARP inhibition , together effective treatment in vivo.
[13]
with a reduced dose of cisplatin (60 mg/m ), improved 2. Materials and methods
2
tolerability and showed improved objective response
[12]
rate, in comparison to olaparib monotherapy in previous 2.1. Materials
phase II clinical trials [14-16] . These findings imply that there Olaparib and cisplatin (powder, 99.70%) were purchased
is obviously room for dose optimization. One solution from MedChemExpress (Monmouth Junction, NJ,
could be the administration of lower doses of cisplatin in USA). Ketamine was purchased from Richter Pharma
more frequent intervals. However, metronomic dosing of AG (Wels, Austria). Xylazine was purchased from
this platinum-based drug would be practically limited, Neocell Pharmaceuticals (Athens, Greece). The LC-MS
since cisplatin is administered intravenously while PARPi grade solvents ammonium acetate, formic acid (FA),

Volume 9 Issue 6 (2023) 27 https://doi.org/10.36922/ijb.0048