Surface Controlled Nanospheres as Drug Carriers for Intravenous and Intranasal Administration
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therapeutic applications as injectable blood-persistent systems for the controlled release of drugs, site-specific drug delivery, or medical imaging. The hydrophilic PEG coating increases the blood half-life of the nanospheres (up to several hours 3), compared to the non-coated ones which are removed within minutes. Mathematical modeling of PEG brushes on hydrophobic surfaces has shown that a long PEG chain length and a high PEG surface density are optimal conditions to prevent protein adsorption 5. However, the invasive intravenous route limits the practical use of numerous therapeutic molecules. Our aim was to widen the application field of these particles and to show that the PEG coating may not only prolongate the blood circulation time, but may also enable the nanospheres to bypass natural barriers, such as the nasal one. Protein delivery from biodegradable polymer systems has been a challenging area of research due to the necessity of improving the delivery of newly developed macromolecular drugs and antigens. The main goals of our work have been to investigate the feasability of encapsulating a model protein, human serum albumin (HSA), into PEG-coated nanospheres of a size of about 200 nm, with good loadings, and to study the main parameters which govern its release from the nanospheres. In a second step, we investigated the encapsulation of tetanus toxoid (IT), a model antigen and the biological fate of the resulting nanospheres. 273 Mat. Res. Soc. Symp. Proc. Vol. 501 © 1998 Materials Research Society
EXPERIMENT Human serum albumin (HSA) and sodium cholate (SC) were purchased from Sigma, France. Tetanus toxoid (IT) saline aqueous solution was donated by the Massachusetts Public Health Biologic Laboratories. It was radiolabelled with 1251. Poly (lactic acid) (PLA) with an average molecular weight (MW) of 450()0 g/mole was obtained from Phusis (Versoud, France). The diblock copolymer monomethoxy polyethylene glycol-poly (lactic acid) (PEG5K-PLA45K) was synthesized as previously described 6 . The average MW of the PEG and PLA blocks were respectively 5000 and 450()0 g/mole. All solvents were analytical grade and bidistilled water was used in all cases. The preparation method of the HSA and YF-loaded nanospheres was an adaptation of the
emulsion method 7 for the preparation of microspheres. Sodium cholate was used as a surfactant and the nanospheres were extensively washed to remove traces of adsorbed surfactant and protein. The nanosphere size distribution was determined by photon correlation spectroscopy (PCS) using a Zetasizer 4 (Malvern Instruments, UK). Their Zeta potential was measured in NaCI 10-3 M using the same apparatus. The chemical composition of the nanosphere top layers was determined using time-of-flight secondary ion mass spectrometry (TOF-SIMS) (Hewlett Packard HP 5950 A) and X-ray photoelectron spectroscopy (XPS). The water vapour (activity 0.98) absorption kinetics in the nanospheres was followed at 37'C using a Sartorius 4201 electromagnetic suspension microbalance. 1251 radiolabelled I
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