Nanoparticles Enhance Therapeutic Efficiency by Selectively Increased Local Drug Dose in Experimental Colitis in Rats

Abstract

Nanoparticles (NP) are proposed for targeted drug delivery to the inflammation site in severe cases of inflammatory bowel disease where state-of-the-art delivery devices fail. FK506 (tacrolimus) entrapped into NP was administered either orally or rectally to male Wistar rats suffering from a preexisting experimental colitis. Clinical activity score, colon/body weight index, and myeloperoxidase activity were determined to assess the inflammation. Tissue penetration experiments elucidated the processes involved in the proposed new therapeutic approach. The therapeutic effects of FK506 solutions as well as FK506-NP by oral route were minor. The myeloperoxidase activity and colon/body weight ratio decreased significantly (P Ͻ 0.05) only after the rectal administration of FK506-NP, whereas treatment by free drug was not different from colitis control in both 2,4,6-trinitrobenzenesulfonic acid and oxazolone colitis model. NP allows an enhanced and selective drug penetration into the inflammation site as opposed to surrounding healthy tissue (healthy: FK506, 109 Ϯ 18 nmol/cm 2 ; FK506-NP, 51 Ϯ 13 nmol/cm 2 ; colitis: FK506, 79 Ϯ 28 nmol/cm 2 ; FK506-NP, 105 Ϯ 24 nmol/cm 2 ), presumably by protecting the encapsulated drug against influences from efflux systems and mucosal metabolism. The relative drug penetration into the inflamed tissue is about 3-fold higher compared with healthy tissue when using NP as drug carriers. The use of drug-loaded NP offers several advantages compared with standard therapeutic strategies such as a higher selectivity in adhesion to and enhanced drug penetration into the inflamed tissue.

Enhanced therapeutic efficacy of budesonide in experimental colitis with enzyme/pH dual-sensitive polymeric nanoparticles

“…According to previous reports, there are several pathophysiological changes due to mucosal inflammation that are involved in preferential NP accumulation, including elevated mucus production, disrupted intestinal barriers, and infiltration of immune-related cells. 32 A subsequent increase in residence time is postulated for NPs compared to existing drug-delivery systems, allowing for a dose reduction. Therefore, size is considered an important factor in the development of colon-specific drug-delivery strategies for the treatment of IBD, because carrier size impacts their accumulation in the inflamed colon.…”

Nanotechnology in cancer therapeutics: bioconjugated nanoparticles for drug delivery

“…It has been used in clinical trials to treat head and neck cancer (intratumoral administration; ref. 15 (20) recently used Tacrolimus (FK506) loaded poly(lactic-co-glycolic acid) nanoparticles entrapped in pH-sensitive microspheres. The FK506 nanoparticles were administered orally or rectally to rats suffering from preexisting experimental colitis.…”

Drug Targeting in IBD Treatment – Existing and New Approaches

“…The importance and tailoring of the physicochemical properties of the DDS according to selected targeting mechanism as well as physiological and patophysiological conditions at the therapeutic site of action will be discussed through design, production and physicochemical characterization of budesonide loaded chitosan-Ca-alginate MPs intended for targeting and treatment of IBD. Particle size: Very well known fact about the particle size of the DDS is that accelerated elimination and premature clearance due to the diarrhea, a major symptom of IBD, will be circumvented by size reduction effect and formulation of MPs or NPs for inflammation targeting (Lamprecht et al, 2005;Nakase et al, 2000;Nakase et al, 2001). In order to achieve improved localization and prolonged residence time due to increased epithelial permeability and enormous immunoregulatory cells activity at the site of inflammation, the beads should have an optimal particle size, probably between 4 and 15 µm (Coppi et al, 2001(Coppi et al, , 2002Lamprecht et al, , 2001a.…”