Development of nanoscale delivery systems for breast cancer treatment

Nanoparticle (NP) assisted diagnosis and drug delivery for antitumor applications have been widely investigated in the past few decades. To date, some of them have been approved for clinical applications and many more of them are under clinical trials. Although some progress has been achieved, it is still necessary to explore novel materials for antitumor applications. The work summarized in this thesis focused on organic NPs, and evaluated engineered polymer NPs and protein-lipid NPs as antitumor drug delivery systems in vitro. And a multifunctional fluorinated NP system was also assessed as theranostic (the combination of therapy and diagnosis) platform. In paper I, two types of 2,2 bis(hydroxymethyl) propionic acid (bis-MPA) based dendritic- linear (DL) polymers were synthesized. One type has the hyperbranched (HB) dendritic structure while the other has dendrons (perfectly branched structures). HBDL and DL materials were compared as drug delivery systems in respect to their synthesis difficulty, quality of micelle formation and efficiency in drug delivery. It was found that HBDL can be synthesized in large scales and drug loaded HBDL tended to have stronger efficacy compared to DL, therefore it is a promising alterative to DL in anticancer drug delivery. Further, in paper II, a detailed study regarding the uptake profile of a bis-MPA based hyperbranched copolymer micelle was conducted. The NP consisted of a Boltorn-H30 core (hyperbranched polyester) and PEG10k hydrophilic tails. It was found that the hyperbranched NP can be internalized into breast cancer cells via clathrin-dependent and macropinocytosis-mediated pathway through a time, concentration and energy dependent process. In paper III, fluorinated copolymers micelles were synthesized and evaluated as theranostic system, which has both diagnostic and therapeutic functions. The consequent micelles were able to load and release doxorubicin (DOX) and demonstrated similar efficacy compared to free (non- formulated) DOX. Also these NPs could generate a detectable signal for 19F-MRI in vitro. In paper IV, unimolecular NPs were developed from polyester based hyperbranched dendritic- linear polymers (HBDLPs). Such micelles were homogenous and did not have critical micelle concentration (CMC). And they were able to load DOX and delivery the drug into breast cancer cells. One HBDLP based NP containing a fluorinated polymer fragment was also synthesized to prove that these unimolecular systems are potentially useful as theranostic platforms. In paper V, histamine functionalized copolymer micelles were developed in order to introduce pH responsive property to NPs and achieve endo-lysosomal escape. These NPs were non-toxic and capable of loading and release DOX. Drug loaded NPs exhibited significant enhanced inhibition of mitochondria function in breast cancer cells during short periods (12 h) compared to free DOX. Although the expected pH responsive behaviour was not observed for the in vitro drug release model, NPs with histamine functionalization demonstrated partly endo-lysosomal escape property, in particular for those with 50% histamine modification. Intracellular tracking of NPs revealed that they could escape from endo-lysosomes and relocate DOX into mitochondria and the nuclei. In paper VI, lipoprotein like NP systems were developed by incorporating Saposin A, phospholipids and selected hydrophobic cargos. Such systems were shown to have promise as drug delivery platforms and to serve as NP based vaccine stabilizers

Kemicentrum vid Lunds universitet : perspektiv på organisation och forskning vid Sveriges första storinstitution

Det är nu 40 år sedan Sveriges första storinstitution, Kemicentrum vid Lunds universitet, bildades 1967. Kemiämnena vid Lunds universitet, kemisektionen vid Lunds Tekniska Högskola och Alnarpsinstitutets mejeriforskning sammanfördes i ett gemensamt byggnadskomplex i norra Lund. Tidigare självständiga institutioner med lång historia och nybildade forskningsinriktningar vid LTH blev nu alla forskningsavdelningar vid en gemensam storinstitution. Denna bok ger en mångsidig beskrivning av Kemicentrum. Bland annat diskuteras vilka faktorer som kan förklara storinstitutionens tillkomst och omvandling över tid. Bokens huvudsakliga fokus ligger på Kemicentrums organisation och forskning