Doctoral defence: Kristina Kiisholts “Peptide-based drug carriers and preclinical nanomedicine applications for endometriosis treatment”

On 28 April at 13:15 Kristina Kiisholts will defend her doctoral thesis “Peptide-based drug carriers and preclinical nanomedicine applications for endometriosis treatment” for obtaining the degree of Doctor of Philosophy (in Biomedical Technology).

Supervisors:
Professor Emeritus Ülo Langel, University of Tartu
Associate Professor Kaido Kurrikoff, University of Tartu
Professor Andres Salumets, University of Tartu
Professor Tambet Teesalu, University of Tartu

Opponent:
Professor Dr Pirjo Laakkonen, University of Helsinki (Finland)

Summary
Endometriosis is a frequent gynecological disease that influences up to 10% of women in reproductive age. The disorder is defined by the presence of uterus inner mucosal layer, endometrium, tissue outside the uterine cavity. The symptoms include chronic pelvic pain and often infertility. The current diagnostic and therapeutic strategies for endometriosis are limited. The treatment often lacks long-term efficacy and causes adverse effects due to systemic administration of pharmaceutics. Therefore, novel treatment strategies for endometriosis are needed. Many highly potential therapeutic targets are in fact located inside the diseased cells. Thus, the biggest challenge for successful treatment of various conditions is that the therapeutic candidates have to reach their intracellular target molecules at the intended target sites.  Hence, the objective of this study was to develop or repurpose peptide-based drug carriers for nanomedical applications mainly focusing on endometriosis.

To start with, highly potent drug delivery vehicles, cell-penetrating peptides (CPPs) were used as short interfering RNA (siRNA) carriers that aim to adjust the therapeutic gene expression levels. First, a series of peptides was designed that display adaptive response to the physical environment and are highly efficient in transporting siRNA into cells both in vitro and in vivo. Second, the therapeutic potential of CPP/siRNA nanoparticles was investigated in cancer and endometriosis preclinical cell culture models. Despite being very efficient in cellular internalization, most CPPs are not tissue specific and might lead to unspecific accumulation of therapeutics in healthy organs when administered in vivo. Thus, as a final step, a series of specific tissue targeting peptides was investigated. PL1 homing peptide proved to be most successful candidate for endometriosis targeting. Silver nanoparticles functionalized with synthetic PL1 peptide showed specific accumulation to 2D and 3D cell cultures and clinical endometriosis tissue samples.

In conclusion, the results of this thesis proved the relevance of downregulating two genes related to growth and progression by CPP/siRNA nanoparticles for endometriosis treatment. Therapeutic effects were enhanced by the combination of nanoparticles with a hormonal drug. In addition, PL1-guided nanoparticles showed high potential in precision diagnosis and tissue specific therapy of endometriosis. All in all, the findings of this thesis propose several peptide-based nanomedical applications for the treatment of endometriosis that suggest translational relevance.