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Rinnakkaistallenteet Terveystieteiden tiedekunta
2019
Retinal bioavailability of liposomal minocycline after sub-conjunctival administration is low
Urtti, Arto
Elsevier BV
Tieteelliset aikakauslehtiartikkelit
© Elsevier Inc
CC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/
http://dx.doi.org/10.1016/j.nano.2018.12.012
https://erepo.uef.fi/handle/123456789/7930
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Accepted Manuscript
Retinal bioavailability of liposomal minocycline after sub- conjunctival administration is low
Arto Urtti
PII: S1549-9634(19)30005-X
DOI: https://doi.org/10.1016/j.nano.2018.12.012
Reference: NANO 1926
To appear in: Nanomedicine: Nanotechnology, Biology, and Medicine Received date: 7 December 2018
Accepted date: 19 December 2018
Please cite this article as: Arto Urtti , Retinal bioavailability of liposomal minocycline after sub-conjunctival administration is low. Nano (2019), https://doi.org/10.1016/
j.nano.2018.12.012
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ACCEPTED MANUSCRIPT
Retinal Bioavailability of Liposomal Minocycline after Sub-conjunctival Administration is Low Arto Urtti*arto.urtti@uef.fi
Laboratory of Biohybrid Technologies (Russian Mega-Grant 14.W03.031.0025), Institute of Chemistry, Saint-Petersburg State University, Russian Federation
Faculty of Pharmacy, University of Helsinki, Finland
School of Pharmacy, University of Eastern Finland, Kuopio, Finland
St. Petersburg State University, Institute of Chemistry, Laboratory of Biohybrid Technologies, Peterhoff, Universitetskii pr. 26, 198504 St. Petersburg, Russia. Tel.: +7 911 843 6029.
Keywords: minocycline; sub-conjunctival; liposome; retinal delivery
Letter to the Editor
Intravitreal injection is the method of choice in the retinal drug delivery, for example, in the treatment of age-related macular degeneration. Obviously, there is scientific interest and clinical need for alternative and less invasive ways to deliver drugs to the retina.
Kaiser et al (1) tested free and liposomal minocycline. For some reason, the liposomes were called as ‘nano-liposomes’, even though the composition, method of preparation (thin film hydration and extrusion) and the result (80 nm diameter, negative zeta-potential of -21 mV) were quite typical for regular liposome formulations. The authors administered the liposomal minocycline to the rats topically, sub-conjunctivally and intravitreally. Surprisingly, the fluorescence images suggest that the highest retinal delivery was reached after sub-conjunctival delivery, and even topical administration resulted in greater delivery than the intravitreal injection. This result is extremely difficult to explain, but the method of analysis was not really quantitative.
Kaiser et al (1) also quantified (mass spectrometry analyses) minocycline in the rat retina after sub-conjunctival injections of free and liposomal minocycline, but not after topical or intravitreal administration. Based on retinal drug concentrations at 30 min and 6 hrs post-dosing, the authors concluded that the retinal bioavailability was 40%. This number far exceeds the previous estimates of about 0.1% for retinal and vitreal bioavailability after sub-conjunctival injections (2,3).
Recalculation of the data reveals that 40% is in fact erroneous and really misleading value. Kaiser et al. (1) injected 20 µl of the minocycline (450 µM) containing liposomes sub-conjunctivally. As the molecular weight of minocycline is 457.4 g/mol, the investigators injected 9 nmol (= 4.2 µg) of the drug. At 30 min and 6 hrs minocycline concentrations in the retina were about 1300 and 1800 ng/ml, respectively. Taking into account the reported dry and wet weights of the rat retina (1.25- 7.5 mg) (4,5), we can calculate that the whole rat retina contained about 1.6-13.5 ng of
minocycline at 30 min and 6 hrs post-dosing. Minocycline quantities in the retina at 30 min and 6 hrs were in the range of 0.04-0.3% of the injected dose.
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Even though retinal delivery of minocycline can be improved with liposomal delivery it is clear that the retinal bioavailability is negligible, approximately 100-1 000 times lower than the reported misleading value of 40%.
Acknowledgement
The support from Russian Government Mega-Grant 14.W03.031.0025 “Biohybrid technologies for modern biomedicine” is acknowledged.
References
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Nanoliposomal minocycline for ocular drug delivery. Nanomedicine: Nanotechnology, Biology and Medicine 2013; 9:130–40.
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Controlled Drug Release from an Ocular Implant: An Evaluation Using Dynamic Three- Dimensional Magnetic Resonance Imaging. Invest. Opthalmol. Vis. Sci. 2004; 45, 2722- 2731.
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4. Shih Y.Y. I., de la Garza B.H., Huang S., Li G., Wang L., Duong T.Q., Comparison of retinal and cerebral blood flow between continuous arterial spin labeling MRI and fluorescent microsphere techniques. J Magn Reson Imagn 2014; 40: 609-615.
5. Winkler B.S., Arnold M.J., Brassell M.A. , Sliter D.A. Glucose Dependence of Glycolysis, Hexose Monophosphate Shunt Activity, Energy Status, and the Polyol Pathway in Retinas Isolated From Normal (Nondiabetic) Rats. Invest Ophthalmol Vis Sci 1997; 38: 62-71.
