Kaminskas Group - Targeted drug delivery - School of Biomedical Sciences

The Targeted Drug Delivery Lab is primarily dedicated to using nano and polymer-technology to improve the delivery of chemotherapeutic drugs towards sites of tumour growth and metastasis, while limiting drug exposure throughout the rest of the body. In particular, our focus is on eliminating cancers that have spread to regional (sentinel) lymph nodes and the lungs with the view to maximise the successful treatment of metastatic cancers and improve survival rates for cancer patients.

The group also have an interest in evaluating how nanoparticles and nanomedicines are cleared from healthy and diseased lungs after inhaled delivery and in understanding the fundamental basis for high inter-individual variability in the pharmacokinetics of macromolecular drugs and nanomedicines.

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 metastasise 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.

Research in our group 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, the 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.

Cancer metastases

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 lymphatic sites of disease progression. This problem can often be overcome by increasing the effective size of the drug, through either polymer modification or association with a nanosized drug carrier. Our lab is involved in evaluating the lymphatic exposure of drugs with indications against lymph-resident diseases and in maximising drug exposure and activity.

Our lab also specialise in characterising the pulmonary lymphatic pharmacokinetics of small and macromolecular drugs/nanomaterials using a large animal model. In Australia, this capability is unique to our lab and work in this area is conducted at a large animal facility in Melbourne. We have the capacity to test the pulmonary lymphatic pharmacokinetics of cytotoxic and radioactive materials.

Improving drug targeting towards the lymphatic system

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. Our 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.

Interindividual variability 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. This is compounded by the fact that macromolecular drugs also tend to exhibit much higher interindividual pharmacokinetic variability than small molecule drugs. At present however, little is known about the biological processes that drive this pharmacokinetic variability, although this will become increasingly important with the rapidly expanding ‘nano-drug’ market. Our lab is therefore focused on understanding why the pharmacokinetics of some macromolecular drugs and nanomedicines differ significantly between individuals, and between males and females, and in identifying whether we can adopt rational approaches to tailor dosing regimes to individual patients without the need for therapeutic drug monitoring.

Group Head

Research staff

Dr Neville Butcher

Senior Research Fellow

School of Biomedical Sciences

PhD students

Chris Subasic
Ashok Kothapalli

View publications on Google Scholar

Poly(HPMA-co-NIPAM) copolymer as an alternative to polyethylene glycol-based pharmacokinetic modulation of therapeutic proteins. Subasic CN, Ardana A, Chan LJ, Huang F, Scoble JA, Butcher NJ, Meagher L, Chiefari J, Kaminskas LM, Williams CC. Int J Pharm. 2021 Oct 25;608:121075. doi: 10.1016/j.ijpharm.2021.121075. Epub 2021 Sep 2. PMID: 34481889
The pharmacokinetics of PEGylated liposomal doxorubicin are not significantly affected by sex in rats or humans, but may be affected by immune dysfunction. Subasic CN, Kuilamu E, Cowin G, Minchin RF, Kaminskas LM. J Control Release. 2021 Sep 10;337:71-80. doi: 10.1016/j.jconrel.2021.07.006. Epub 2021 Jul 7. PMID: 34245788
The Impact of Polymer Size and Cleavability on the Intravenous Pharmacokinetics of PEG-Based Hyperbranched Polymers in Rats. Marasini N, Fu C, Fletcher NL, Subasic C, Er G, Mardon K, Thurecht KJ, Whittaker AK, Kaminskas LM. Nanomaterials (Basel). 2020 Dec 8;10(12):2452. doi: 10.3390/nano10122452. PMID: 33302413 Free PMC article.
Cetuximab Exhibits Sex Differences in Lymphatic Exposure after Intravenous Administration in Rats in the Absence of Differences in Plasma Exposure. Kuilamu E, Subasic C, Cowin GJ, Simpson F, Minchin RF, Kaminskas LM. Pharm Res. 2020 Oct 19;37(11):224. doi: 10.1007/s11095-020-02945-2. PMID: 33078255
The impact of size and charge on the pulmonary pharmacokinetics and immunological response of the lungs to PLGA nanoparticles after intratracheal administration to rats. Haque S, Pouton CW, McIntosh MP, Ascher DB, Keizer DW, Whittaker MR, Kaminskas LM. Nanomedicine. 2020 Nov;30:102291. doi: 10.1016/j.nano.2020.102291. Epub 2020 Aug 22. PMID: 32841737
Aerosol Pirfenidone Pharmacokinetics after Inhaled Delivery in Sheep: a Viable Approach to Treating Idiopathic Pulmonary Fibrosis. Kaminskas LM, Landersdorfer CB, Bischof RJ, Leong N, Ibrahim J, Davies AN, Pham S, Beck S, Montgomery AB, Surber MW. Pharm Res. 2019 Dec 10;37(1):3.
dendPoint: a web resource for dendrimer pharmacokinetics investigation and prediction. Kaminskas LM, Pires DEV, Ascher DB. Sci Rep. 2019 Oct 29;9(1):15465.
Local inflammation alters the lung disposition of a drug loaded pegylated liposome after pulmonary dosing to rats. Haque S, Feeney O, Meeusen E, Boyd BJ, McIntosh MP, Pouton CW, Whittaker M, Kaminskas LM. J Control Release. 2019 May 29;307:32-43.
*A 30 kDa polyethylene glycol-enfuvirtide complex enhances the exposure of enfuvirtide in lymphatic viral reservoirs in rats. Kaminskas LM, Williams CC, Leong NJ, Chan LJ, Butcher NJ, Feeney OM, Porter CJH, Tyssen D, Tachedjian G, Ascher DB. Eur J Pharm Biopharm. 2019 Apr;137:218-226.
Reducing Dendrimer Generation and PEG Chain Length Increases Drug Release and Promotes Anticancer Activity of PEGylated Polylysine Dendrimers Conjugated with Doxorubicin via a Cathepsin-Cleavable Peptide Linker. Mehta D, Leong N, McLeod VM, Kelly BD, Pathak R, Owen DJ, Porter CJH, Kaminskas LM. Mol Pharm. 2018 Oct 1;15(10):4568-4576.
Doxorubicin Conjugation and Drug Linker Chemistry Alter the Intravenous and Pulmonary Pharmacokinetics of a PEGylated Generation 4 Polylysine Dendrimer in Rats. Leong NJ, Mehta D, McLeod VM, Kelly BD, Pathak R, Owen DJ, Porter CJH, Kaminskas LM. J Pharm Sci. 2018 Sep;107(9):2509-2513.
A comparison of the lung clearance kinetics of solid lipid nanoparticles and liposomes by following the 3H-labelled structural lipids after pulmonary delivery in rats. Haque S, Whittaker M, McIntosh MP, Pouton CW, Phipps S, Kaminskas LM. Eur J Pharm Biopharm. 2018 Apr;125:1-12
Microfluidic preparation of drug-loaded PEGylated liposomes, and the impact of liposome size on tumour retention and penetration. Dong YD, Tchung E, Nowell C, Kaga S, Leong N, Mehta D, Kaminskas LM, Boyd BJ. J Liposome Res. 2019 Mar;29(1):1-9.
Influence of Size and Shape on the Biodistribution of Nanoparticles Prepared by Polymerization-Induced Self-Assembly. Kaga S, Truong NP, Esser L, Senyschyn D, Sanyal A, Sanyal R, Quinn JF, Davis TP, Kaminskas LM, Whittaker MR. Biomacromolecules. 2017 Dec 11;18(12):3963-3970
An Evaluation of Optimal PEGylation Strategies for Maximizing the Lymphatic Exposure and Antiviral Activity of Interferon after Subcutaneous Administration. Chan LJ, Feeney OM, Leong NJ, McLeod VM, Porter CJH, Williams CC, Kaminskas LM. Biomacromolecules. 2017 Sep 11;18(9):2866-2875.
Effect of increased surface hydrophobicity via drug conjugation on the clearance of inhaled PEGylated polylysine dendrimers. Haque S, McLeod VM, Jones S, Fung S, Whittaker M, McIntosh M, Pouton C, Owen DJ, Porter CJH, Kaminskas LM. Eur J Pharm Biopharm. 2017 Oct;119:408-418
*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
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.
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

Contact

Associate Professor Lisa Kaminskas Room 517, Skerman Building (#65)

Find out more about our diverse range of research interests.

Research with us

Kaminskas Group - Targeted drug delivery

Improving chemotherapeutic drug targeting to sites of primary cancer and secondary cancer metastases

Improving drug targeting towards the lymphatic system

Understanding the mechanisms by which inhaled nanoparticles are cleared from the lungs

Interindividual variability in macromolecule pharmacokinetics

Group Head

Research staff

Dr Neville Butcher

PhD students

Contact