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Targeting metastatic cancer using dendrimer-based drug delivery systems
thesisposted on 2017-01-23, 21:32 authored by Ryan, Gemma
Effective treatment of metastatic tumours is hampered by poor distribution of small molecule chemotherapeutic drugs to distal sites of metastatic growth. This thesis has examined the potential for nano-sized drug carriers, and in particular dendritic polymers or dendrimers to enhance the exposure of chemotherapeutics to lymphatic and lung resident cancer metastases and to promote benefits in treatment efficacy against these hard-to-treat tumours. Initial studies compared the lymphatic distribution of a series of nanochemotherapeutics following subcutaneous (SC) administration. Conjugation of a model chemotherapeutic drug (doxorubicin; DOX) to a PEGylated dendrimer (12 nm diameter) resulted in the greatest exposure of DOX to the lymphatic system when compared to DOX encapsulated within a (~100 nm) PEGylated liposome, various selfassembled micellar (6 nm) systems or a control formulation of DOX in saline. The advantage provided by the dendrimer formulation appeared to reflect a combination of efficient interstitial convection and selective lymphatic absorption. Improved lymphatic exposure of a second chemotherapeutic, methotrexate (MTX), following conjugation to a PEGylated dendrimer scaffold was subsequently demonstrated and also shown to improve the treatment of lymph node metastases following IV and SC administration when compared to a solution formulation of MTX. In spite of improved lymphatic exposure, however, interaction of the carboxyl group in MTX with a putative receptor at the SC injection site significantly limited interstitial drainage of the MTX conjugated dendrimer. Subsequent studies revealed that this interaction could be reduced (and lymphatic drainage improved) by conjugation of MTX to the dendrimer with a linker of lower molecular weight, thereby withdrawing the MTX interaction site into the PEG corona of the dendrimer, and also by coadministration with macromolecules such as dextrans and albumin, that appear to block the interaction site. The second aspect of this thesis examined the potential for dendrimers to selectively target secondary cancers in the lung and the pulmonary lymphatic system following administration to the lungs. Initial studies revealed that the degree of dendrimer PEGylation significantly influenced lung residence time, dendrimer absorption and in vivo dendrimer stability following administration to the lungs. Dendrimers with a layer of surface conjugated PEG of relatively low molecular weight (200 Da) were more efficiently absorbed from the lungs, but were also highly metabolised. In comparison systems derived with higher molecular weight PEG (570 Da+) were retained for longer and were more stable, but were less readily absorbed. Drug conjugation to the larger PEGylated dendrimer was subsequently shown to reduce pulmonary toxicity and to enhance the treatment of lung-resident metastases after instillation to the lungs of rats when compared to IV or pulmonary administration of a DOX solution. Surprisingly, the contribution of the pulmonary lymphatic system to dendrimer absorption from the lung was minimal, presumably reflecting limited access to pulmonary lymphatics as these are largely absent from alveoli. In summary, this thesis describes the use of PEGylated dendrimers as a vehicle to promote the exposure of chemotherapeutics to the lymphatic system, highlights the potential of this approach to improve the treatment of lymph node resident tumours and provides proof of concept data to support the use of dendrimer-based drug delivery systems to provide improved treatment options for lung resident tumours.
Awards: Vice-Chancellor’s Commendation for Doctoral Thesis Excellence in 2015.