Unique insights into the intestinal absorption, transit, and subsequent biodistribution of polymer-derived microspheres

Abstract

Polymeric microspheres (MSs) have received attention for their potential to improve the delivery of drugs with poor oral bioavailability. Although MSs can be absorbed into the absorptive epithelium of the small intestine, little is known about the physiologic mechanisms that are responsible for their cellular trafficking. In these experiments, nonbiodegradable polystyrene MSs (diameter range: 500 nm to 5 μm) were delivered locally to the jejunum or ileum or by oral administration to young male rats. Following administration, MSs were taken up rapidly (≤5 min) by the small intestine and were detected by transmission electron microscopy and confocal laser scanning microscopy. Gel permeation chromatography confirmed that polymer was present in all tissue samples, including the brain. These results confirm that MSs (diameter range: 500 nm to 5 μm) were absorbed by the small intestine and distributed throughout the rat. After delivering MSs to the jejunum or ileum, high concentrations of polystyrene were detected in the liver, kidneys, and lungs. The pharmacologic inhibitors chlorpromazine, phorbol 12-myristate 13-acetate, and cytochalasin D caused a reduction in the total number of MSs absorbed in the jejunum and ileum, demonstrating that nonphagocytic processes (including endocytosis) direct the uptake of MSs in the small intestine. These results challenge the convention that phagocytic cells such as the microfold cells solely facilitate MS absorption in the small intestine.oral delivery | uptake mechanism B eginning in the 1960s, several groups (1-7) demonstrated that the small intestine could absorb microparticles with a diameter >1 μm, challenging dogma that the small intestine could only absorb small macromolecules. After this discovery, researchers began engineering microspheres (MSs) to deliver drugs with poor water solubility (8-10), poor gastrointestinal permeability (11), or poor oral bioavailability (8,9,(12)(13)(14)(15) to the small intestine. MS-based oral drug delivery systems (ODDSs) can be made from biodegradable polymers (12,(16)(17)(18), nondegradable polymers (19-21), and polysaccharides (22, 23) and can be engineered to carry polypeptides (18,24,25) and other molecules (26, 27). The motivation for using microparticulate-based ODDSs is to improve the oral bioavailability of drugs by enhancing their delivery and transit through the absorptive epithelium of the small intestine. This work may ultimately enable patients to take medications orally instead of relying on daily or weekly injections or other, less convenient routes of administration (28).More than five decades after Sanders and Ashworth discovered that the small intestine can engulf large particles (1), little is known today about the cellular mechanisms or physiologic pathways that facilitate the absorption, transit, and biodistribution of microparticles that are delivered to the small intestine. Nonetheless, the diverse physiology and multitude of cell types in the small intestine likely play a central role in these processes. The absorp...

Delivery strategies to enhance oral vaccination against enteric infections

“…In addition to the role of size in regulating the potential for trans-epithelial uptake, the ability of particles to migrate through the pores in the mucus is dependent on both size and surface electrochemical properties [33,191]. While M cells remain a key target for particulate oral vaccines, it was recently shown that particles of 1-5 μm in size were taken up across the jejunum and ileum via non phagocytic processes, suggesting that particle uptake is not solely via M cells [192]. In the latter study, particle uptake was greater for 0.5 μm and 1 μm particles than for those of 2 μm or 5 μm in size.…”

Agmatine prevents acute chlorpromazine-induced neurotoxicity in rats

“…Poznato je da davanje HPZ dovodi do njegove akumulacije u ćelijama i tkivima, a time i u organizmu (37). Rezultati naše studije pokazuju da 24 h nakon akutne primene AGM sa HPZ dolazi do značajne redukcije koncentracije HPZ u mozgu u odnosu na životinje koje su dobile samo HPZ, što pokazuje da prisustvo AGM smanjuje i odlaže resorpciju HPZ (Tabela I).…”

Drug- not carrier-dependent haematological and biochemical changes in a repeated dose study of cyclosporine encapsulated polyester nano- and micro-particles: Size does not matter

“…Although statistically significant differences were seen between nCsA and mCsA, the numerical differences in absolute values between these two groups were not large especially between groups in the high dose cohort (Figure 3). It has been reported in the literature that particle sizes < 2 µm are absorbed through the lymphatic system in lower numbers than particles up to 500 nm in size (Mathiowitz et al, 1997, Desai et al, 1996Reineke et al, 2013). The wide size distribution range in our mCsA preparation and comparable serum CsA concentration with either mCsA or nCsA, prompted us to do differential centrifugation to apportion the contribution made of nanoparticles to the mCsA preparation (SI Figure 2a-c).…”

“…A dose dependent increase in serum CsA levels was noted across the doses and mCsA generally showed much higher levels (almost comparable to nCsA) than anticipated owing to the presence of a significant proportion of nanoparticles in mCsA preparations ( Figure 3; SI Figure 2a-c). Although there is no agreement on the cut-off for particle size for optimal peroral absorption, it is a relative phenomenon whereby smaller is generally believed to be better (Mittal et al, 2007;Reineke et al, 2013).…”

“…There has been much debate in the literature surrounding the question of particle size cut-off of non-conventional (nanoparticle) formulations for drug uptake following oral dosing; recent studies suggest smaller (0.5 µm) vehicles lead to greater up-take compared to larger (5 µm) (Reineke et al, 2013). Indeed the vast majority of reports on non-conventional CsA preparations has focussed on drug bioavailability enhancement in vivo (Italia et al, 2007;Ankola et al, 2010Ankola et al, & 2011Park et al, 2013) without consideration of possible influence on organ or system physiology and function (Lucas et al, 2005;Moss and Siccardi 2014).…”