Universität zu Köln

Kovalyk, Xenia ORCID: 0009-0006-4143-5686 (2025). Theranostic biodegradable particles for image-guided intraperitoneal drug delivery: from synthesis to preclinical validation. PhD thesis, Universität zu Köln.

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Abstract

Peritoneal carcinomatosis (PC) results from the spread of tumor cells to the peritoneal surface in the abdomen. While intraperitoneal (i.p.) chemotherapy enables high local drug concentrations, its effectiveness is limited by rapid clearance. Significant gaps remain in understanding the routes of drug absorption (lymphatic versus blood) and pharmacokinetics following i.p. administration, particularly when complex delivery systems such as nano- and microparticles (NPs and MPs) are involved. This thesis explores novel biodegradable drug delivery systems (DDS) designed for sustained i.p. release and reduced systemic toxicity. The in vivo behavior of NPs and MPs was studied, focusing on how physicochemical properties such as size, charge, and composition influence absorption into lymph, peritoneal organ uptake, as well as lymphatic clearance and pharmacokinetics, following i.p. administration. By integrating advanced imaging modalities (e.g., magnetic resonance imaging (MRI), computer tomography (CT), single-photon emission CT (SPECT)), the biodistribution and degradation of DDS were quantitatively monitored. The work centers on two chemotherapeutic agents, paclitaxel (PTX) and cis–diamminedichloroplatinum (cisplatin, CDDP), representing hydrophobic and hydrophilic drugs, respectively. Poly(lactic-co-glycolic acid) (PLGA)-based core-shell particles loaded with PTX and containing either perfluorooctylbromide (PFOB) for 19F-MRI or iodinated oil octan-2-yl 2,3,5-triiodobenzoate (TIBO) for dual-energy CT (DECT) imaging were synthesized and optimized for controlled size and drug loading. A novel 19F-MRI acquisition technique (Balanced Spiral Spectroscopic Imaging, BaSSI) enabled sensitive in vivo tracking of fluorinated DDS, while DECT provided complementary visualization and quantification of iodinated particles. 19F-MRI of an animal injected with PFOB capsules revealed prolonged peritoneal retention and gradual degradation near the injection site. TIBO capsules, detectable by DECT due to their iodine content, exhibited higher PTX loading and slow release kinetics with similar biodistribution patterns. Both systems demonstrated particle aggregation at injection sites with significant retention up to 18 days and particle presence in tumor-prone regions. Additionally, collagen-poly(glutamic acid) NPs were developed for complexation and sustained release of platinum-based drugs. Hydrophilic platinum-based drugs such as CDDP were complexed with free functional groups abundant in the NPs which enabled high CDDP loading with sustained release. Radiolabeling with [111In]InCl3 facilitated sensitive SPECT/CT imaging, to longitudinally assess NP biodistribution and clearance, highlighting the potential for lymphatic targeting. Notable retention in the peritoneal cavity and uptake in metastatic target organs were observed. Overall, this work provides a versatile platform combining advanced imaging and tailored DDS to optimize i.p. drug delivery in a theranostic approach. The findings emphasize the importance of balancing particle size, surface properties, and drug loading to enhance anti-tumor effectiveness, biodistribution and peritoneal retention through the careful selection of DDS. Such optimization could improve treatment outcomes for PC. Future studies employing imageable tumor models will be beneficial to validate therapeutic efficacy and translate these systems into clinical application.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Kovalyk, Xenia xeniakovalyk@web.de https://orcid.org/0009-0006-4143-5686 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-809719
Date:	2025
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Physical Chemistry
Subjects:	Natural sciences and mathematics Chemistry and allied sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language image-guided drug delivery UNSPECIFIED peritoneal carcinomatosis UNSPECIFIED biodegradable polymers UNSPECIFIED
Date of oral exam:	24 October 2025
Referee:	Name Academic Title Grüll, Holger Prof. Dr. Neumaier, Bernd Prof. Dr. Wickleder, Mathias Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80971