Treatment of Experimental Arthritis with Stealth-Type Polymeric Nanoparticles Encapsulating Betamethasone Phosphate

Abstract

We examined the therapeutic activity of betamethasone disodium 21-phosphate (BP) encapsulated in biocompatible and biodegradable blended nanoparticles of poly (d,l-lactic/glycolic acid) (PLGA)/poly(d,l-lactic acid) (PLA) homopolymers and polyethylene glycol (PEG)-block-PLGA/PLA copolymers (stealth nanosteroid) in experimental arthritis models. Various stealth nanosteroids with a size of 45 to 115 nm were prepared and then intravenously administered to rats with adjuvant arthritis (AA) rats and mice with anti-type II collagen antibody-induced arthritis (AbIA). The accumulation of stealth nanoparticles with Cy7 in inflamed joints was determined using an in vivo imaging system. The type A stealth nanosteroid, composed of PLA (2.6 kDa) and PEG (5 kDa)-PLA (3 kDa), with a PEG content of 10% and a diameter of 115 nm, exhibited the highest anti-inflammatory activity. In AA rats, a 35% decrease in paw inflammation was obtained in 1 day and maintained for 9 days with a single injection of the type A stealth nanosteroid (40 μg of BP), whereas the same does of nonstealth nanosteroid and 3 times higher free BP showed a significantly weaker response. In AbIA mice, a single injection of the type A stealth nanosteroid (3 μg of BP) resulted in complete remission of the inflammatory response after 1 week. Furthermore, in AbAI mice, the accumulation of type A stealth nanoparticles in inflamed joints was shown to parallel the severity of inflammation. The observed strong therapeutic benefit obtained with the type A stealth nanosteroid in experimental arthritis may have been due to prolonged blood circulation and targeting to the inflamed joint in addition to its sustained release in situ.