Browsing by Subject "chemistry - Radiochemistry"

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  • Imlimthan, Surachet (Helsingin yliopisto, 2021)
    Cancer is a critical health concern worldwide. Although significant progress in cancer diagnosis and therapy has been made to date, the lack of efficient delivery of active compounds to the target site and adverse systemic effects remain a major challenge in cancer treatment. For those reasons, different therapeutic strategies have been developed to improve the target specificity and reduce side effects in conventional therapy. Nanomedicines are innovative nanoparticulate drug delivery systems constructed from biocompatible, biodegradable, and nontoxic materials. Nanoparticles can transport diagnostic and therapeutic agents with increased bioavailability, reduced dosing frequency, and less off-target side effects. Recently, cellulose nanocrystals (CNC NPs) and lignin nanoparticles (LNPs) have attracted attention as abundant natural nanomaterials that can be derived from various bioresources, especially plant-based lignocellulosic biomass. CNC NPs and LNPs have been intensively explored as material scaffolds in numerous biomedical applications due to their unique physicochemical and biological properties. Nuclear molecular imaging techniques, including single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are non-invasive and sensitive imaging technologies that allow the tracking of a tracer dose of radiopharmaceuticals in vivo to determine their target occupancy, circulation, biodistribution profiles, and elimination kinetics. Nanomaterials tagged with a radioactive label can be traced after systemic administration through the detection of gamma photons emitted by the radioactive isotopes outside the body (single γ photon for SPECT and annihilation of two anti-parallel 511 keV photons for PET). Moreover, several radioisotopes can concomitantly release diagnostic γ radiation and ionizing particles (α or β-) during their decay, enabling the consolidation of diagnostic imaging and radiotherapy. The combination of imaging labels and therapeutic agents into a single nanoparticle platform creates a theranostic nanosystem, which can be used for simultaneous imaging and therapy of cancer. This thesis aimed to develop theranostic nanoparticle drug delivery systems based on CNC NPs and LNPs. The project comprised of several studies: 1) radiolabeling chemistry development, 2) in vitro cytotoxicity and cellular uptake investigation, 3) in vivo biodistribution and imaging studies in tumor-bearing animal models with the developed tracers, and 4) a theranostic nanosystem development and biological evaluation based on the observations from 1–3. Firstly, CNC- and LNP-based imaging probes for nuclear and optical imaging were developed for the in vitro and in vivo investigation using two modification strategies: site-specific hydrazone linkage to the terminal aldehyde of the CNC and non-site-specific conjugation using CDI activation. Both multimodal CNC NPs and LNPs demonstrated low cytotoxicity and favorable interactions with macrophage and cancer cell lines. Following extensive validation in material characterization and in vitro cell models, radiometal chelator DOTA-modified CNC NPs from both synthetic pathways were selected to further explore the in vivo behavior through the labeling with diagnostic radionuclide 111In in both healthy and 4T1 breast tumor-bearing mouse models. The ex vivo biodistribution and SPECT/CT imaging revealed comparable pharmacokinetic profiles where the accumulation of all developed 111In-labeled CNC NPs was primary in the lung, liver, and spleen, which are the clearance organs of nontargeted nanoparticles. Due to high retention of the CNC in the lung capillaries, theranostic CNC NPs were further developed for co-delivery of radiotherapeutic 177Lu and chemotherapeutic vemurafenib to target YUMM1.G1 metastatic melanoma in the lung through vascular trapping. The theranostic CNC NPs exhibited excellent radiolabel stability and sustained drug release profiles in vitro. The therapeutic studies also showed that the lifespan of tumor-bearing animals treated with theranostic CNC NPs was increased about twice from the median survival time of animals receiving only the vehicle or CNC NPs carrying only a single component of the theranostic system. In conclusion, the work presented in this thesis demonstrates the successful development of novel CNC- and LNP-based molecular imaging nanoprobes and the theranostic CNC NPs for the delivery of radio- and chemotherapeutic agents with enhanced therapeutic efficacy compared to the conventional chemotherapy in metastatic melanoma. The studies provide a breakthrough on the development of systemically administered CNC drug delivery systems and warrant further investigation on the potential of CNC NPs as a renewable scaffold for theranostic drug delivery systems.