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Niosome encapsulation of a doxorubicin polymer conjugate
AURACIAm
ELSEVIER
European
Journal of Pharmaceutical
Sciences
4 Suppl. (1996) S28
JAAAIIAL
OI
PEARMACEUI' SCIENCES
Niosome encapsulation of a doxorubicin polymer conjugate I.F. Uchegbu*,
E. Gianasi, F. Cociancinch,
A.T. Florence,
R. Duncan
Centre for Polymer Therapeutics, School of Pharmacy, University of London, London WCIN IAX, UK
In an attempt at anti-cancer drug targeting with doxorubicin (DOX), a DOX N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer showing tumour tropism in animals [I] and designed to release DOX following intracellular cleavage by lysosomal enzymes [l] is now in early clinical development [2]. This macromolecular prodrug targets tumours by an enhanced penetration and retention (EPR) effect in which the leaky vasculature and decreased lymphatic drainage within tumours results in high intratumoural levels of the drug which may be elevated further by increasing the polymer molecular weight [3]. To reduce renal clearance of PKl and thus increase tumour accumulation, a non-ionic surfactant vesicle (niosome) formulation of PKl has been developed [4]. Here we have studied the effect of method of preparation on PKl loading, niosome, size, stability and DOX release. Niosomes were prepared from a hexadecyl poly-5oxyethylene diglycerol ether, a hexadecyl ether a stearyl poly-5oxyethylene ether, sorbitan monostearate or sorbitan monopalmitate in a 1: 1 molar ratio with cholesterol, various amounts of Solulan C24 (cholesteryl poly-24-oxyethylene ether) and 2% dicetyl phosphate. The incubation of PKl with performed niosomes at room temperature resulted in less entrapment that when the freeze drying [S] technique was used (3 vs. 64%) showing minimal passive association of PKl with surfactant bilayers. Freeze drying lead to a 2-fold increase in size (150 vs. 370 nm). Filtration (0.22 pm), however resulted in a 40% decrease in mean size (270 nm).
*Corresponding
author.
0928~0987/96/$32.00 0 PII SO928-0987(96)00034-6
1996 Elsevier Science B.V. All rights reserved
Span 60 niosomes were found to be stable at 4 and 25°C retaining 75% of encapsulated material after 28 days. The incubation of PKl niosomes with plasma at 37°C resulted in the release of only 0.2% DOX after 72 h, whereas the incubation with lysosomal enzymes resulted in cleavage of PKl and the release of 7% DOX after 72 h. These results indicate an unusually high stability for the niosomal formulation and suggest that the active drug will only be available in vivo following niosomal degradation, intracellular uptake and cleavage of the drug. Despite the absence of cryoprotectant disaccharides in the formulation, niosomes remained in the submicron size range when levels of solulan C24 were at or below 19%. It is possible that the hydrophilic polymer itself, acts to a certain extent as a cryoprotectant. In general, an increase in surfactant alkyl chain length and the shift from the more fluid poly-5-oxyethylene head group to the less fluid diglycerol head group, increased PKl entrapment and niosome size.
References Cl1L.W. Seymour,
K. Ulbrich, P.S. Steyger, M. Brereton, V Subr, J. Strohalm and R. Duncan (1994) Br. J. Cancer, 70: 6366641. 121P.A. Vasey, R. Duncan and S.B. Kaye (1995) Eur. J. Cancer 31A (suppl 15): s193. [31 L.W. Seymour, Y. Miyamoto, H. Maeda, M. Brereton, J. Strohalm, K. Ulbrich and R. Duncan (1995). Eur. J. Cancer 3 IA: 766-770. r41 I.F. Uchegbu, F. Cociacinch, A.T. Florence and R. Duncan. British application number 9600471.8. (Nov): 979-984. PI C. Kirby, G. Gregoriadis (1984), Biotechnology
ELSEVIER
European
Journal of Pharmaceutical
Sciences
4 Suppl. (1996) S28
JAAAIIAL
OI
PEARMACEUI' SCIENCES
Niosome encapsulation of a doxorubicin polymer conjugate I.F. Uchegbu*,
E. Gianasi, F. Cociancinch,
A.T. Florence,
R. Duncan
Centre for Polymer Therapeutics, School of Pharmacy, University of London, London WCIN IAX, UK
In an attempt at anti-cancer drug targeting with doxorubicin (DOX), a DOX N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer showing tumour tropism in animals [I] and designed to release DOX following intracellular cleavage by lysosomal enzymes [l] is now in early clinical development [2]. This macromolecular prodrug targets tumours by an enhanced penetration and retention (EPR) effect in which the leaky vasculature and decreased lymphatic drainage within tumours results in high intratumoural levels of the drug which may be elevated further by increasing the polymer molecular weight [3]. To reduce renal clearance of PKl and thus increase tumour accumulation, a non-ionic surfactant vesicle (niosome) formulation of PKl has been developed [4]. Here we have studied the effect of method of preparation on PKl loading, niosome, size, stability and DOX release. Niosomes were prepared from a hexadecyl poly-5oxyethylene diglycerol ether, a hexadecyl ether a stearyl poly-5oxyethylene ether, sorbitan monostearate or sorbitan monopalmitate in a 1: 1 molar ratio with cholesterol, various amounts of Solulan C24 (cholesteryl poly-24-oxyethylene ether) and 2% dicetyl phosphate. The incubation of PKl with performed niosomes at room temperature resulted in less entrapment that when the freeze drying [S] technique was used (3 vs. 64%) showing minimal passive association of PKl with surfactant bilayers. Freeze drying lead to a 2-fold increase in size (150 vs. 370 nm). Filtration (0.22 pm), however resulted in a 40% decrease in mean size (270 nm).
*Corresponding
author.
0928~0987/96/$32.00 0 PII SO928-0987(96)00034-6
1996 Elsevier Science B.V. All rights reserved
Span 60 niosomes were found to be stable at 4 and 25°C retaining 75% of encapsulated material after 28 days. The incubation of PKl niosomes with plasma at 37°C resulted in the release of only 0.2% DOX after 72 h, whereas the incubation with lysosomal enzymes resulted in cleavage of PKl and the release of 7% DOX after 72 h. These results indicate an unusually high stability for the niosomal formulation and suggest that the active drug will only be available in vivo following niosomal degradation, intracellular uptake and cleavage of the drug. Despite the absence of cryoprotectant disaccharides in the formulation, niosomes remained in the submicron size range when levels of solulan C24 were at or below 19%. It is possible that the hydrophilic polymer itself, acts to a certain extent as a cryoprotectant. In general, an increase in surfactant alkyl chain length and the shift from the more fluid poly-5-oxyethylene head group to the less fluid diglycerol head group, increased PKl entrapment and niosome size.
References Cl1L.W. Seymour,
K. Ulbrich, P.S. Steyger, M. Brereton, V Subr, J. Strohalm and R. Duncan (1994) Br. J. Cancer, 70: 6366641. 121P.A. Vasey, R. Duncan and S.B. Kaye (1995) Eur. J. Cancer 31A (suppl 15): s193. [31 L.W. Seymour, Y. Miyamoto, H. Maeda, M. Brereton, J. Strohalm, K. Ulbrich and R. Duncan (1995). Eur. J. Cancer 3 IA: 766-770. r41 I.F. Uchegbu, F. Cociacinch, A.T. Florence and R. Duncan. British application number 9600471.8. (Nov): 979-984. PI C. Kirby, G. Gregoriadis (1984), Biotechnology