Nanoparticles and Medicines Design

3/9/2020 12:15 - 12:50

Pharmaceutical nanotechnology involves the formation of drug loaded nanoparticles from polymers, lipids and surface active agents 1.  Such nanoparticles have been used to formulate approved drugs, which target a particular clinical problem, such as: avoiding cardiotoxicity in the case of Doxil and avoiding hypersensitivity reactions in the case of the excipient used in Abraxane 2, 3.  To gain approval, provide real patient benefit and encourage prescribing, it is essential that nanomedicines are sufficiently differentiated from a clinical perspective and preclinical data should support such potential differentiation, prior to proceeding to expensive clinical testing.  An increase in bioavailability, for example, is often an insufficient driver for clinical development. 

Over the last two decades, we have designed a large variety of self-assembling polymers 4-6 and peptides 7, 8 and used these to develop nanomedicines, which may be administered via the intravenous 7-9 oral 10-12 and intranasal 13 routes.  The Molecular Envelope Technology (MET) is one such self-assembling polymer system and the MET has been used to prepare preclinical stage nanomedicines that are well differentiated in a manner that is relevant to their clinical use.  These nanomedicines show advantageous alterations in drug biodistribution and additional studies have illuminated some interesting mechanisms 7, 12, 14. MET-enabled nanomedicines will be discussed in the talk.  Additionally diagnostic platforms are now being investigated within our laboratory 15.

References 
1. Uchegbu, I. F.; Schätzlein, A. G.; Chen, W. P.; Lalatsa, A., Fundamentals of pharmaceutical nanoscience. Springer: New York, 2013.

2. Sleep, D.  Albumin and its application in drug delivery. Expert Opin Drug Deliv 2015, 12, 793-812.

3. Gabizon, A.; Shmeeda, H.; Barenholz, Y.  Pharmacokinetics of pegylated liposomal doxorubicin - Review of animal and human studies. Clin. Pharmacokinet. 2003, 42, 419-436.

4. Wang, W.; McConaghy, A. M.; Tetley, L.; Uchegbu, I. F.  Controls on polymer molecular weight may be used to control the size of palmitoyl glycol chitosan polymeric vesicles. Langmuir 2001, 17, 631-636.

5. Brown, M. D.; Schatzlein, A.; Brownlie, A.; Jack, V.; Wang, W.; Tetley, L.; Gray, A. I.; Uchegbu, I. F.  Preliminary characterization of novel amino acid based polymeric vesicles as gene and drug delivery agents. Bioconjug. Chem. 2000, 11, 880-891.

6. Cheng, W. P.; Gray, A. I.; Tetley, L.; Hang, T. L. B.; Schatzlein, A. G.; Uchegbu, I. F.  Polyelectrolyte nanoparticles with high drug loading enhance the oral uptake of hydrophobic compounds. Biomacromolecules 2006, 7, 1509-1520.

7. Mazza, M.; Notman, R.; Anwar, J.; Rodger, A.; Hicks, M.; Parkinson, G.; McCarthy, D.; Daviter, T.; Moger, J.; Garrett, N.; Mead, T.; Briggs, M.; Schatzlein, A. G.; Uchegbu, I. F.  Nanofiber-based delivery of therapeutic peptides to the brain. ACS Nano 2013, 7, 1016-26.

8. Lalatsa, A.; Schatzlein, A. G.; Garrett, N. L.; Moger, J.; Briggs, M.; Godfrey, L.; Iannitelli, A.; Freeman, J.; Uchegbu, I. F.  Chitosan amphiphile coating of peptide nanofibres reduces liver uptake and delivers the peptide to the brain on intravenous administration. J Control Release 2015, 197, 87-96.

9. Fisusi, F. A.; Siew, A.; Chooi, K. W.; Okubanjo, O.; Garrett, N.; Lalatsa, K.; Serrano, D.; Summers, I.; Moger, J.; Stapleton, P.; Satchi-Fainaro, R.; Schatzlein, A. G.; Uchegbu, I. F.  Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels - A Strategy for Brain Cancer Treatments. Pharm Res 2016, 33, 1289-303.

10. Serrano, D. R.; Lalatsa, A.; Dea-Ayuela, M. A.; Bilbao-Ramos, P. E.; Garrett, N. L.; Moger, J.; Guarro, J.; Capilla, J.; Ballesteros, M. P.; Schatzlein, A. G.; Bolas, F.; Torrado, J. J.; Uchegbu, I. F.  Oral particle uptake and organ targeting drives the activity of amphotericin B nanoparticles. Mol Pharm 2015, 12, 420-31.

11. Siew, A.; Le, H.; Thiovolet, M.; Gellert, P.; Schatzlein, A.; Uchegbu, I.  Enhanced oral absorption of hydrophobic and hydrophilic drugs using quaternary ammonium palmitoyl glycol chitosan nanoparticles. Molecular Pharmaceutics 2012, 9, 14-28.

12. Soundararajan, R.; Sasaki, K.; Godfrey, L.; Odunze, U.; Fereira, N.; Schatzlein, A.; Uchegbu, I.  Direct in vivo evidence on the mechanism by which nanoparticles facilitate the absorption of a water insoluble, P-gp substrate. Int J Pharm 2016, 514, (1), 121-132.

13. Godfrey, L.; Iannitelli, A.; Garrett, N. L.; Moger, J.; Imbert, I.; King, T.; Porreca, F.; Soundararajan, R.; Lalatsa, A.; Schatzlein, A. G.; Uchegbu, I. F.  Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia. J Control Release 2017, 270, 135-144.

14. Garrett, N. L.; Lalatsa, A.; Uchegbu, I.; Schatzlein, A.; Moger, J.  Exploring uptake mechanisms of oral nanomedicines using multimodal nonlinear optical microscopy. J Biophotonics 2012, 5, 458-68.

15. Hobson, N.; Weng, J.; Siow, B.; Veiga, C.; Ashford, M.; Nguyen, T. K.; Schatzlein, A. G.; Uchegbu, I. F.  Clustering iron oxide nanoparticles leads to high contrast images. Nanomedicine (Lond) 2019, 14, 1135-1152.

Professor Andreas Schätzlein, Chair in Translational Therapeutics,, UCL School of Pharmacy