Nicolazzo Lab

Joe Nicolazzo

Dr Joseph Nicolazzo
Senior Lecturer
Tel: 9903 9605



Joseph Nicolazzo is a Senior Lecturer at the Faculty of Pharmacy and Pharmaceutical Sciences at Monash University, Melbourne. He completed his undergraduate and graduate studies at Monash University before moving into an academic role where he teaches into both the Bachelor of Pharmacy and Bachelorof  Pharmaceutical  Science degrees, is the Leader of the Drug Delivery stream of the Bachelor of Pharmacy degree and is an active researcher within Monash Institute of Pharmaceutical Sciences. Joseph's research programs focus on the molecular mechanisms facilitating the transport of endogenous and exogenouscompounds  across  the blood-brain barrier (BBB), how these processes alter in neurodegenerative diseases, and unravelling how biochemical alterations at the BBB contribute to neurodegenerative diseases, with a particular emphasis on Alzheimer's disease. Joseph is a CI on 4 NHMRC grants and has attractedfunding  from  various philanthropic organisations including The Mason Foundation, The Bethlehem Griffiths Research Foundation and ANZ Trustees. The work from his group has resulted in 45+ peer reviewed publications and the graduation of 4 PhD students, 1 Masters student and 6 Honours students. Josephis Treasurer  of  the Australasian Pharmaceutical Science Association, is an Editorial Board Member of Journal of Pharmaceutical Sciences and Pharmaceutical Research, and has recently been appointed as the Review Editor of Pharmaceutical Research.

Project Areas

My group focusses primarily on the role of the blood-brain barrier (BBB) as a regulatory interface between the brain and the blood, and (i) how this biological membrane controls the trafficking of both endogenous and exogenous molecules into and out of the brain, (ii) how alterations to the BBB inAlzheimer's  disease  impact  on CNS exposure of therapeutic agents, and (iii) unravelling novel approaches to enhance the expression and function of membrane transporters responsible for the impaired BBB clearance of the neurotoxic β-amyloid observed in Alzheimer's disease. In addition, my groupalso exploits  the buccal  mucosa as an alternative route for delivery of otherwise poorly-absorbed therapeutic agents, including peptides and proteins.

Nicolazzo et al. Ther Deliv 1:595-611 (2010)

The blood-brain barrier (BBB), formed by the endothelial cells lining the cerebral microvessels, forms a major obstacle in drug delivery to the CNS, but also controls the trafficking of endogenous molecules both into and out of the CNS, a process which may contribute to neurological diseases.

Major Reviews

1. Mehta DC, Short JL, Hilmer S, Nicolazzo JA. Drug access to the central nervous system in Alzheimer's disease: preclinical and clinical insights (2014, accepted)

2. Pan Y, Khalil H, Nicolazzo JA. The impact of docosahexaenoic acid on Alzheimer's disease: is there a role of the blood-brain barrier? Curr Clin Pharmacol (2014, accepted)

3. Caon T, Jin L, Simoes CMO, Norton RS, Nicolazzo JA. Approaches for enhancing the buccal mucosal delivery of peptide and protein therapeutics. Pharm Res (2014, accepted)

4. Nicolazzo JA, Banks WA. Decreased blood-brain barrier expression of P-glycoprotein in Alzheimer's disease: impact on pathogenesis and brain access of therapeutic agents. Ther Deliv 2:841-844 (2011)

5. Nicolazzo JA, Mehta DC. Transport of drugs across the blood-brain barrier in Alzheimer's disease. Ther Deliv 1:595-611 (2010)

6. Nicolazzo JA, Katneni K. Drug transport across the blood-brain barrier and the impact of breast cancer resistance protein (ABCG2). Curr Top Med Chem 9:130-147 (2009)

Molecular factors governing BBB drug transport

Given the restrictive nature of the BBB, the ability of pre-clinical drug candidates to enter the CNS and exert their pharmacological activity following systemic administration is often hindered. To this end, our laboratory focusses on understanding some of the mechanisms facilitating or preventingmolecular  access  into the CNS, including membrane influx and efflux transporters and intracellular carrier proteins. Using in vitro, in situ and in vivo approaches, we also collaborate with various drug discovery scientists to assess the potential of novel drug candidates to traverse the BBB and exploitendogenous  trafficking  processes to enhance the CNS delivery of otherwise poorly-permeable compounds.

An understanding of molecular factors governing BBB transport (e.g. passive diffusion, binding to membrane influx transporters or interaction with intracellular carrier proteins) can guide chemical modifications which lead to enhanced in vitro and in vivo BBB transport, as exemplified with rimantadine    (RIM)    which exhibits a greater interaction with a saturable membrane transporter relative to amantadine (AMA) and a preferential brain uptake in vivo (Kooijmans, Mol Pharm (2012)).

Key Publications

1. Mountford S, Albiston AL, Charman WN, Ng L, Holien JK, Parker MW, Nicolazzo JA, Thompson PE, Chai SY. Synthesis, structure-activity relationships and brain uptake of a novel series of benzopyran inhibitors of insulin-regulated aminopeptidase. J Med Chem 57:1368-1377 (2014)
2. Mehta DC, Short JL, Nicolazzo JA. Memantine transport across the mouse blood-brain barrier is mediated by a cationic influx H+ antiporter. Mol Pharm10:4491-4498 (2013)
3. Bergström CAS, Charman SA, Nicolazzo JA. Computational prediction of CNS drug exposure based on a novel in vivo dataset.Pharm  Res  29:3131-3142 (2012)
4. Kooijmans SAA, Senyschyn D, Mezhiselvam MM, Morizzi J, Charman SA, Weksler B, Romero IA, Couraud PO, Nicolazzo JA. The involvement of a Na+ and Cl-dependent transporter in the brain uptake of amantadine and rimantadine. Mol Pharm 9:883-893 (2012)
5. Jin L, LiJ, Nation  RL,  Nicolazzo JA. Brain penetration of colistin in mice assessed by a novel high performance liquid chromatographic technique. Antimicrob Agents Chemother 53:4247-4251 (2009)
6. Nicolazzo JA, Nguyen TT, Katneni K, Steuten JA, Smith G, Jarrott B, Callaway JK, Charman SA. Pharmacokineticsand brain  uptake  of AM-36, a novel neuroprotective agent, following intravenous administration to rats. J Pharm Pharmacol 60:171-178 (2008)

Impact of disease on BBB drug transport

While significant progress has been made into understanding how the BBB controls xenobiotic access into the CNS under normal conditions, less is known about how alterations to the BBB occurring as a result of both neurological and non-neurological disease impact on CNS disposition of drugs. Many diseasesare  reported  to be associated with a "generalized BBB disruption" and this has resulted in the dogma that disease is often associated with increased CNS access of drugs. However, a careful evaluation of how different disease states actually impact on the CNS disposition of drugs is lacking. To this end,we  have  demonstrated that systemic bacterial infection can increase the BBB permeability to large molecular weight antibiotics, however, this appears to be bacterial infection-specific. Furthermore, using a mouse model of Alzheimer's disease, we have demonstrated that the rate of BBB transport of passively-diffusingdrugs  is  actually decreased, which argues against the unproven dogma that CNS exposure is increased in Alzheimer's disease. Therefore, an area of research within our laboratory which is gaining increasing interest is to investigate how CNS exposure of drugs alters in different disease states, and themechanisms  responsible  for the observed alterations.

Using the 3xTg mouse model of Alzheimer's disease, we have demonstrated that the BBB transport of passively-diffusing drugs is substantially decreased in Alzheimer's disease, likely as a result of increased cerebrovascular basement membrane thickening (Mehta, Pharm Res 2013; Mehta, J Pharm Biomed Anal    2013)

Key Publications

1. Mehta DC, Short JL, Hilmer S, Nicolazzo JA. Drug access to the central nervous system in Alzheimer's disease: preclinical and clinical insights. Pharm Res (2014, accepted)
2. Mehta DC, Short JL, Nicolazzo JA. Reduced CNS exposure of memantine in a triple transgenic mouse model of Alzheimer's disease assessed using a novel LC-MS technique. J Pharm Biomed Anal 85:198-206 (2013)
3. Mehta DC, Short JL, Nicolazzo JA. Altered brain uptake of therapeutics in a tripletransgenic  mouse  model of Alzheimer's disease. Pharm Res 30:2868-2879 (2013)
4. Jin L, Nation RL, Li J, Nicolazzo JA. Species-dependent lipopolysaccharide-induced blood-brain barrier disruption: amelioration by colistin in vitro and in vivo. Antimicrob Ag Chemother 57:4336-4342 (2013)
5. JinL, Li J, Nation  RL,  Nicolazzo JA. The effect of systemic infection induced by Pseudomonas aeruginosa on the brain uptake of colistin in mice. Antimicrob Agents Chemother 56:5240-5246 (2012)
6. Jin L, Li J, Nation RL, Nicolazzo JA. The impact of P-glycoprotein inhibition and lipopolysaccharide administrationon the  blood-brain  barrier transport of colistin in mice. Antmicrob Agents Chemother 55:502-507 (2011)

The BBB as a target for the treatment of Alzheimer's disease

Alzheimer's disease is the most common form of dementia and is associated with brain accumulation of the neurotoxic β-amyloid (Aβ) peptide. In the majority of people with Alzheimer's disease, there is decreased clearance of Aβ from the brain, including decreased efflux of this peptide across the BBB.Indeed,  the  BBB expression of the membrane proteins responsible for the trafficking of Aβ across the BBB (P-glycoprotein, P-gp) and low density lipoprotein receptor-related protein 1 (LRP-1) is decreased in people with AD and in mouse models of AD. Our laboratory is therefore focusing on novel approachesto increase  the  expression and function of P-gp and LRP-1 and in collaboration with Professor William Banks (University of Washington), we are identifying whether such approaches lead to increased BBB efflux of Aβ. Together with Dr Jennifer Short (Drug Discovery Biology, MIPS), we are also assessingwhether such  approaches  lead to improved cognitive function in mouse models of AD. To date, we have demonstrated that our approach can increase the BBB expression of P-gp and LRP-1, leading to improved BBB efflux of Aβ and improved cognitive function. This novel area of research has the potential tolead to unexploited  targets  at the BBB which can be pharmacologically manipulated to reverse Aβ accumulation and cognitive dysfunction.

The BBB efflux of Aβ is mediated by LRP-1 and P-gp, the expression of which is decreased in Alzheimer's disease. By upregulating the BBB expression of LRP-1 and P-gp, the BBB efflux of Aβ is enhanced. Molecular targets at the BBB may therefore be exploited to decrease the brain parenchymal accumulation    of    Aβ and restore cognitive function.

Key Publications

1. Nicolazzo JA, Banks WA. Decreased blood-brain barrier expression of P-glycoprotein in Alzheimer's disease: impact on pathogenesis and brain access of therapeutic agents. Ther Deliv 2:841-844 (2011)
2. Nicolazzo JA, Mehta DC. Transport of drugs across the blood-brain barrier in Alzheimer's disease. Ther Deliv 1:595-611 (2010)

Buccal mucosal drug delivery

While oral administration is the preferred route of delivering medicines to patients to maximise compliance, the harsh conditions of the gastrointestinal tract and first pass metabolism often limit the bioavailability of many medicines, particularly peptides and proteins. Our laboratory has thereforefocused  on  the buccal mucosa as an alternative route of drug delivery for molecules that would otherwise exhibit poor absorption if administered via the traditional oral route. The benefits of the buccal mucosa including direct drainage into the jugular vein, avoidance of first pass metabolism and easeof administration,  make  this route suitable for many drug candidates. Using in vitro and in vivo models, we have demonstrated that various formulation approaches can either enhance or reduce the rate of absorption of molecules through the buccal mucosa. We also have a major interest in exploiting the"reservoir" capacity  of  the buccal mucosa as a means of controlling the release of drugs into the systemic circulation, an approach which may be of significant interest for molecules with short plasma half-lives such as peptides and proteins.

Administration of small and large molecular weight compounds to the buccal mucosa leads to therapeutically-relevant plasma concentrations in vivo, which are modifiable with various formulation approaches.

Key Publications

1. Caon T, Jin L, Simoes CMO, Norton RS, Nicolazzo JA. Approaches for enhancing the buccal mucosal delivery of peptide and protein therapeutics. Pharm Res (2014, accepted)
2. Caon T, Pan Y, Simoes CMO, Nicolazzo JA. Exploiting the buccal mucosa as an alternative route for the delivery of donepezil hydrochloride. J Pharm Sci 103:1643-1651 (2014)
3. Meng-Lund E, Jacobsen J, Jin L, Janfelt C, Holm R, Müllertz A, Nicolazzo JA. Azone® decreases the buccal mucosalpermeation  of  diazepam in a concentration-dependent manner via a reservoir effect. J Pharm Sci 103:1133-1141 (2014)
4. Heemstra LB, Finnin BC, Nicolazzo JA. The buccal mucosa as an alternative route for the systemic delivery of risperidone. J Pharm Sci 99:4584-4592 (2010)
5. Nicolazzo JA, MannilaJ. Buccal  delivery  systems. In Morishita M, Park K (Eds.) Biodrug Delivery Systems: Fundamentals, Applications and Clinical Development. Informa, New York:119-137 (2009)
6. Nicolazzo JA, Reed BL, Finnin BC. Buccal penetration enhancers – How do they really work? J Control Rel 105:1-15 (2005)
7.  Nicolazzo  JA, Reed BL, Finnin BC. Enhanced buccal mucosal retention and reduced buccal permeability of estradiol in the presence of padimate O and Azone® – a mechanistic study. J Pharm Sci 94: 873-882 (2005)

Group Members

Major Collaborating Laboratories: Professor William Banks (University of Washington, USA), Professor Ben Boyd, Professor Mary Collins (University of Sydney), Professor Raymond Norton, Professor Chris Porter, Professor Colin Pouton, Dr Johan Rosengren (University of Queensland), AssociateProfessor  Martin  Scanlon, Dr Jennifer Short

Post Docs: Dr Liang Jin
Research Assistants: Danielle Senyschyn
PhD Students: Mitchell McInerney, Gordon Lee, Yijun Pan, Durgesh Tiwari

Current Major Funding

NHMRC Project Grant (1081733): δ-containing GABAA receptors as targets for neuroprotection (2015-2018)
NHMRC Project Grant (1066369): Novel peptide modulators for the pharmacological manipulation of feeding (2014-2016)
NHMRC Project Grant (1048855): A novel approach for the treatment of Alzheimer's disease (2013-2015)
NHMRC Project Grant (1042481): Overcoming the delivery hurdle for peptidetherapeutics:  new  treatment for autoimmune diseases (2013-2015)