Biomacromolecules 2002, 3, 1154-1162
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Stepwise Self-Assembled Poly(amidoamine) Dendrimer and Poly(styrenesulfonate) Microcapsules as Sustained Delivery Vehicles Ajay J. Khopade and Frank Caruso* Max Planck Institute of Colloids and Interfaces, D-14424 Potsdam, Germany Received May 10, 2002; Revised Manuscript Received July 18, 2002
Hollow microcapsules comprised of poly(styrenesulfonate) (PSS) and a fourth generation poly(amidoamine) dendrimer (4G PAMAM) were prepared by depositing PSS/4G PAMAM multilayers on melamine formaldehyde (MF) colloid particles by the layer-by-layer self-assembly technique and subsequently dissolving the templated cores. The PSS/4G PAMAM layers were unstable toward the core removal procedure (pH ∼ 1), resulting in a low yield of intact hollow capsules (80% free sulfonate groups of the DS in the capsules preloaded with DS, which most likely were responsible for reswelling of the capsules due to their hydration. The release experiments were first conducted in 0.01 M HCl solution, in which DOX is soluble. The capsules
Self-Assembled Microcapsules
incorporating DOX (with preloaded DS) showed a burst release of ∼22%, followed by an additional release of 5-8% over 16 h (Figure 4). The burst release was due to immediate release of surface adsorbed DOX molecules or molecular aggregates in acidic conditions as a result of displacement of the DOX cation (-NH4+) by H+. The remaining loaded DOX was assumed to be well entrapped within capsules forming tightly bound ionic complexes with DS. Complete release would most likely require capsule degradation and/ or high ionic strength conditions. The release experiments conducted in 0.154 M NaCl showed more than 90% release in 4-5 h, demonstrating the strong influence of ion-exchange phenomenon on release rate. Similar release profiles have been reported for DOX-loaded dextran microspheres (Sephadex SP C-25, Pharmacia NJ).21 The fluorescent peak of DOX at 628 nm appeared as a shoulder in the release medium after 16 h, which suggests that a small amount of DOX still remained bound to polyelectrolytes present in the release medium as a result of capsule destruction. Importantly, by using this ion-exchange loading/release approach, the rate of drug release can be significantly prolonged (and controlled) from several seconds and minutes, as is typically observed with linear polyelectrolyte multilayers,20 to hours. Prolonged release times are often required in drug delivery to avoid multiple dosage regimens. Conclusions We have shown that hollow PSS/4G PAMAM microcapsules can be obtained after removal of the MF core from multilayer-coated particles under conditions that enhance the PSS-PSS binding interactions within the multilayers, thus improving their stability. Electrostatic, hydrophobic, and a combination of these interactions were exploited to facilitate the formation of microcapsules. Depending on the approach employed, hollow capsules with different yields and capsule membrane characteristics were obtained. A combination of electrostatic and hydrophobic forces was found to be the most optimal approach for preparing stable capsules in high yield. The capsule stabilization pathways reported here might also be applicable to a range of other capsules, even those of linear polyelectrolytes. We also showed that the drug sequestering property of DS-encapsulated in the DOXstabilized capsules could be successfully used to control loading and release of DOX. We are currently exploiting the presence of dendrimer in the PSS/4G PAMAM capsules to prepare cross-linked membrane films that are amenable to surface modification for studying their interactions with biological surfaces. Acknowledgment. P. Schuetz and A. Heilig are thanked for assistance with TEM and AFM measurements, respectively. E. Poptoshev and T. Cassagneau are thanked for critical reading of the manuscript. H. Mo¨hwald is thanked for supporting the work within the MPI-Interface department. A. J. Khopade acknowledges the Alexander von Humboldt Foundation for a research fellowship. This work was funded by the BMBF under the Biofuture initiative.
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(23) Gao, C. Y.; Moya, S.; Lichtenfeld, H.; Casoli, A.; Fiedler, H.; Donath, E.; Mo¨hwald, H. Macromol. Mater. Eng. 2001, 286, 355. (24) The MF core assists in the formation of PSS capsules by forming MF-PSS bridges. A. J. Khopade and F. Caruso, manuscript in preparation. (25) Khalifa, M. E. Chem. Anal. 1996, 41, 357. (26) Jiang, L.; Yang, D. H.; Chen, S. B. Macromolecules 2001, 34, 3730. (27) Lo¨sche, M.; Schmitt, J.; Decher, G.; Bouwman, W. G.; Kjaer, K. Macromolecules 1998, 31, 8893. Dubois, E.; Boue, F. Macromolecules 2001, 34, 3684. (28) rms values were calculated by SFM from the flat portions of the capsules where there was no overlapping of membranes. (29) Philippova, O. E.; Pieper, T. G.; Sitnikova, N. L.; Starodoubtsev, S. G.; Khokhlov, A. R.; Kilian, H. G. Macromolecules 1995, 28, 3925. (30) Caruso, F.; Lichtenfeld, H.; Donath, E.; Mo¨hwald, H. Macromolecules 1999, 32, 2317.
Khopade and Caruso (31) Leporatti, S.; Gao, C.; Voigt, A.; Donath, E.; Mohwald, H. Eur. Phys. J. E 2001, 5, 13. (32) Karukstis, K. K.; Thompson, E. H. Z.; Whiles, J. A.; Rosenfeld, R. J. Biophys. Chem. 1998, 73, 249. (33) Theoretical calculation: The mass of the capsule is 4πr2hF ) 83.1 × 10-15 g and the volume of the capsule is 4/3πr3 ) 22.5 × 10-12 cm3, where r ) 1.75 × 10-4 cm, h ) 1.8 × 10-7 cm, and F ) 1.2 g cm-3. The amount of DS that can be loaded per capsule at different equilibrium ) 22.5 × 10-15 g and the total mass of a DS loaded capsule ) 105.6 × 10-15 g. Molecular weight (Mw) (DOX) ) 544, Mw (DS) ) 10 000. Sulfonate groups per DS molecule are ∼75; thus the theoretical DOX/DS (w/w) ratio ) 4:1, assuming 1:1 DOX/ sulfonate binding.
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