Kaminskas, Lisa - University of Queensland - School of Biomedical Sciences

研究领域

Improving chemotherapeutic drug targeting to sites of primary cancer and secondary cancer metastases The metastatic spread of cancer accounts for 90% of all cancer related deaths. Cancers may metastasize either via the blood and target distant organs (such as the lungs and bone marrow) or via the lymph and lodge initially in local lymph nodes. Currently, the pharmaceutical management of metastatic cancer is via the intravenous administration of small molecule chemotherapeutic drugs that distribute throughout the entire body, leading to severe drug related side effects with no guarantee of killing the cancer. Lisa’s research is therefore focused on using nanotechnology and drug formulation approaches to improve the treatment of metastatic cancers by: 1) developing nanochemotherapeutic platforms to enhance the delivery of cancer chemotherapy drugs towards primary tumours and sites of cancer metastasis; 2) optimising the biopharmaceutical properties of protein-based cancer therapeutics and immunomodulators to maximise exposure to lymphatic metastases. To this end, her lab specialises in characterising the lymphatic and tumour biodistribution of novel nanochemotherapeutics and PEGylated proteins and in evaluating the biopharmaceutical behavior of inhaled chemotherapeutic nanomedicines. Improving drug targeting towards the lymphatic system In addition to being a major pathway by which cancers spread throughout the body, the lymphatic system is also the site of pathogenesis for a wide range of infections and hard to treat diseases (such as HIV and filariasis). In most cases, lymphatic diseases are treated ‘via the blood’ with small molecule drugs that inefficiently access the lymphatic sites of disease progression. This problem can be overcome by increasing the effective size of the drug, through either polymer modification or association with a nanosized drug carrier. Lisa’s lab is involved in evaluating the lymphatic exposure of drugs with indications against lymph-resident diseases and in maximising drug exposure and activity. Understanding the mechanisms by which inhaled nanoparticles are cleared from the lungs With increasing interest in the development of inhalable nanomedicines, there is a growing emphasis on understanding how, and how rapidly inhaled nanoparticles are ultimately cleared from the lungs. Lisa’s lab has expertise in characterising the mechanisms by which biodegradable/bioerodible nanoparticle and colloid-based drug carriers are cleared from the lungs and the impact of lung disease on the clearance kinetics and pathways. Gender differences in macromolecule pharmacokinetics A gender bias in biomedical research has been evident for decades, where drug development has traditionally been undertaken using predominantly male cells and subjects. However, gender and the female hormone cycle can have profound impacts on the pharmacokinetics of many small molecule drugs which can affect drug activity and toxicity profiles. It is for this reason that women generally experience many more adverse drug reactions than men. This is also true for some macromolecular drugs and nanomedicines, including protein therapeutics and liposomes. At present however, little is known about the biological processes that drive gender differences in the pharmacokinetics of macromolecular drugs and nanomedicines, although this will become increasingly important with the rapidly expanding ‘nano-drug’ market. Lisa’s lab is therefore also focussed on understanding why the pharmacokinetics of some macromolecular drugs and nanomedicines differ significantly between males and females, and in identifying whether the magnitude of this effect can be predicted prior to clinical trials.

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Disposition and Safety of Inhaled Biodegradable Nanomedicines: Opportunities and Challenges. Haque S, Whittaker MR, McIntosh MP, Pouton CW, Kaminskas LM. Nanomedicine. 2016;12(6): 1703-24. Conjugation of 10 kDa Linear PEG onto Trastuzumab Fab' Is Sufficient to Significantly Enhance Lymphatic Exposure while Preserving in Vitro Biological Activity. Chan LJ, Ascher DB, Yadav R, Bulitta JB, Williams CC, Porter CJ, Landersdorfer CB, Kaminskas LM. Mol Pharm. 2016;13(4): 1229-41. A Comparison of the Pharmacokinetics and Pulmonary Lymphatic Exposure of a Generation 4 PEGylated Dendrimer Following Intravenous and Aerosol Administration to Rats and Sheep. Ryan GM, Bischof RJ, Enkhbaatar P, McLeod VM, Chan LJ, Jones SA, Owen DJ, Porter CJ, Kaminskas LM. Pharm Res. 2016;33(2): 510-25. Molecular weight (hydrodynamic radius) dictates the systemic pharmacokinetics and tumour disposition of polyPEG star polymers. Khor SY, Hu J, McLeod VM, Quinn JF, Williamson M, Porter CJH, Whittaker MR, Kaminskas LM, Davis TP. Nanomedicine. 2015; 11(8): 2099-108. From sewer to saviour – targeting the lymphatic system to promote drug disposition and activity. Trevaskis NT, Kaminskas LM, Porter CJH. Nature Reviews Drug Discovery. 2015; 14(11); 781-803. PEGylated interferon displays differences in plasma clearance and bioavailability between male and female mice and between female immunocompetent C57Bl/6J and athymic nude mice. Landersdorfer CB, Caliph SM, Shackleford DM, Ascher DB, Kaminskas LM. J Pharm Sci. 2015 May;104(5):1848-55. Spray-Dried Influenza Antigen with Trehalose and Leucine Produces an Aerosolizable Powder Vaccine Formulation that Induces Strong Systemic and Mucosal Immunity after Pulmonary Administration. Sou T, Morton DA, Williamson M, Meeusen EN, Kaminskas LM, McIntosh MP. J Aerosol Med Pulm Drug Deliv. 2015; 28 (5): 361-71. PEGylation does not significantly change the initial intravenous or subcutaneous pharmacokinetics or lymphatic exposure of trastuzumab in rats but increases plasma clearance after subcutaneous administration. Chan LJ, Bulitta JB, Ascher DB, Haynes JM, McLeod VM, Porter CJ, Williams CC, Kaminskas LM. Mol Pharm. 2015;12(3):794-809. Optimal PEGylation can improve the exposure of interferon in the lungs following pulmonary administration. Mcleod VM, Chan LJ, Ryan GM, Porter CJ, Kaminskas LM. J Pharm Sci. 2015;104(4):1421-30. Methotrexate-conjugated PEGylated dendrimers show differential patterns of deposition and activity in tumour-burdened lymph nodes after intravenous and subcutaneous administration in rats. LM Kaminskas, VM McLeod, DB Ascher, GM Ryan, S Jones, J Haynes, N Trevaskis, L Chan, E Sloan, B Finnin, M Williamson, T Velkov, B Kelly, ED Williams, DJ Owen, CJH Porter. Mol Pharm. 2014. 2015;12(2):432-43 Pulmonary administration of a doxorubicin-conjugated dendrimer enhances drug exposure to lung metastases and improves cancer therapy. Kaminskas LM, McLeod VM, Ryan GM, Kelly BD, Haynes JM, Williamson M, Thienthong N, Owen DJ, Porter CJ. J Control Release. 2014;183:18-26 The Lymphatic System Plays a Major Role in the Intravenous and Subcutaneous Pharmacokinetics of Trastuzumab in Rats. Dahlberg AM, Kaminskas LM, Smith A, Nicolazzo JA, Porter CJ, Bulitta JB, McIntosh MP. Mol Pharm. 2014; 11: 496-504. PEGylated polylysine dendrimers increase lymphatic exposure to doxorubicin when compared to PEGylated liposomal and solution formulations of doxorubicin. Ryan GM, Kaminskas LM, Bulitta JB, McIntosh MP, Owen DJ, Porter CJ. J Control Release. 2013;172(1):128-36. Pulmonary administration of PEGylated polylysine dendrimers: absorption from the lung versus retention within the lung is highly size-dependent. Ryan GM, Kaminskas LM, Kelly BD, Owen DJ, McIntosh MP, Porter CJ. Mol Pharm. 2013;10(8):2986-95. PEGylation of interferon α2 improves lymphatic exposure after subcutaneous and intravenous administration and improves antitumour efficacy against lymphatic breast cancer metastases. Kaminskas LM, Ascher DB, McLeod VM, Herold MJ, Le CP, Sloan EK, Porter CJ. J Control Release. 2013;168(2):200-8. Association of chemotherapeutic drugs with dendrimer nanocarriers: an assessment of the merits of covalent conjugation compared to noncovalent encapsulation. Kaminskas LM, McLeod VM, Porter CJ, Boyd BJ. Mol Pharm. 2012; 9(3):355-73. Doxorubicin-conjugated PEGylated dendrimers show similar tumoricidal activity but lower systemic toxicity when compared to PEGylated liposome and solution formulations in mouse and rat tumor models. Kaminskas LM, McLeod VM, Kelly BD, Cullinane C, Sberna G, Williamson M, Boyd BJ, Owen DJ, Porter CJ. Mol Pharm. 2012; 9(3):422-32. Dendrimer pharmacokinetics: the effect of size, structure and surface characteristics on ADME properties. Kaminskas LM, Boyd BJ, Porter CJ. Nanomedicine (Lond). 2011; 6(6):1063-84. A comparison of changes to doxorubicin pharmacokinetics, antitumor activity, and toxicity mediated by PEGylated dendrimer and PEGylated liposome drug delivery systems. Kaminskas LM, McLeod VM, Kelly BD, Sberna G, Boyd BJ, Williamson M, Owen DJ, Porter CJ. Nanomedicine. 2012; 8(1):103-11. Targeting the lymphatics using dendritic polymers (dendrimers). Kaminskas LM, Porter CJ. Adv Drug Deliv Rev. 2011; 63(10-11):890-900.