Sistemas para liberação colônica: Uma alternativa para a veiculação de fármacos para efeito local ou sistêmico

Problems related to the systemic administration of drugs, such as biodistribution, difficulty of targeting, necessity of high doses to achieve adequate levels of the drug in specific sites, toxicity, and undesirable side effects have lead to the development of systems able to direct the drug to specific sites in the body. Among the possible organs to the targeting of drugs, the colon can be used for local and systemic therapies. By developing such systems some models have been tested, using pH dependent release, release controlled by enzymatic degradation, time controlled release systems and pressure controlled release systems. This review presents an overview of the colonic release of drugs and the strategies used to achieve such targeting.

Fe-bLf nanoformulation targets survivin to kill colon cancer stem cells and maintains absorption of iron, calcium and zinc

To validate the anticancer efficacy of alginate-enclosed, chitosan-conjugated, calcium phosphate, iron-saturated bovine lactoferrin (Fe-bLf) nanocarriers/nanocapsules (NCs) with improved sustained release and ability to induce apoptosis by downregulating survivin, as well as cancer stem cells.

INVITRO ACTION OF VASOPRESSIN ON WATER-ABSORPTION BY RAT COLON

The action of vasopressin on water absorption was studied in vitro in the colon of rats, weighing approximately 250 g. Everted sacs of intestinal segments (ascending and descending colons) prepared with mucosa only were used. Vasopressin (10 mM) significantly stimulated water absorption in both the proximal (4.85 +/- 3.78 vs 1.51 +/- 1.16 ml/mg) and distal (10.39 +/- 3.52 vs 7.22 +/- 3.58 ml/mg) colon, which corresponds to an increase of 220% and 50%,respectively. The results indicate the need for a study of the possible physiological function of vasopressin in enhancing intestinal water absorption, when it is released in response to plasma hyperosmolarity.

In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract

An in vitro colon extended physiologically based extraction test (CEPBET) which incorporates human gastrointestinal tract (GIT) parameters (including pH and chemistry, solid-to-fluid ratio, mixing and emptying rates) was applied for the first time to study the bioaccessibility of brominated flame retardants (BFRs) from the 3 main GIT compartments (stomach, small intestine and colon) following ingestion of indoor dust. Results revealed the bioaccessibility of γ-HBCD (72%) was less than that for α- and β-isomers (92% and 80% respectively) which may be attributed to the lower aqueous solubility of the γ-isomer (2 μg L−1) compared to the α- and β-isomers (45 and 15 μg L−1 respectively). No significant change in the enantiomeric fractions of HBCDs was observed in any of the studied samples. However, this does not completely exclude the possibility of in vivo enantioselective absorption of HBCDs, as the GIT cell lining and bacterial flora – which may act enantioselectively – are not included in the current CE-PBET model. While TBBP-A was almost completely (94%) bioaccessible, BDE-209 was the least (14%) bioaccessible of the studied BFRs. Bioaccessibility of tri-hepta BDEs ranged from 32–58%. No decrease in the bioaccessibility with increasing level of bromination was observed in the studied PBDEs.

Novel alginate-enclosed chitosan–calcium phosphate-loaded iron-saturated bovine lactoferrin nanocarriers for oral delivery in colon cancer therapy

Aim: To develop polymeric-ceramic nanocarriers (NCs) in order to achieve oral delivery of the anticancer neutraceutical iron-saturated bovine lactoferrin (Fe-bLf) protein.

Materials & methods: Fe-bLf or paclitaxel (Taxol®) were adsorbed onto calcium phosphate nanocores, enclosed in biodegradable polymers chitosan and alginate. The Fe-bLf or Taxol-loaded NCs indicated as AEC–CP–Fe-bLf or AEC–CP–Taxol NCs, respectively, were made by combination of ionic gelation and nanoprecipitation. Size distribution, morphology, internalization and release profiles of the NCs were studied along with evaluation of in vitro and in vivo anticancer activities and compared with paclitaxel.

Results: AEC–CP–Fe-bLf NCs obtained spherical morphology and showed enhanced endocytosis, transcytosis and anticancer activity in Caco-2 cells in vitro. AEC–CP–Fe-bLf NCs were supplemented in an AIN 93G diet and fed to mice in both prevention and treatment human xenograft colon cancer models. AEC–CP–Fe-bLf NCs were found to be highly significantly effective when given orally, as a pretreatment, 1 week before Caco-2 cell injections. None of the mice from the AEC–CP–Fe-bLf NC-fed group developed tumors or showed any signs of toxicity, while the mice fed the control AIN 93G diet showed normal tumor growth. Fe-bLf or Taxol, when given orally in a diet as nanoformulations post-tumor development, showed a significant regression in the tumor size with complete inhibition of tumor growth later, while intratumoral injection of Taxol just delayed the growth of tumors. The pharmacokinetic and bioavailability studies indicated that nanoformulated Fe-bLf was predominantly present on tumor cells compared to non-nanoformulated Fe-bLf. Fe-bLf-loaded NCs were found to help in absorption of iron and thus may have utility in enhancing the iron uptake during iron deficiency without interfering with the absorption of calcium.

Conclusion: With the promising results of our study, the future potential of NC-loaded Fe-bLf in chemoprevention and in the treatment of human colon cancer, deserves further investigation for translational research and preclinical studies of other malignancies.

Locked nucleic acid modified bi-specific aptamer-targeted nanoparticles carrying survivin antagonist towards effective colon cancer therapy

We investigated the anti-cancer activity of alginate coated chitosan nanoparticles (CHNP) encapsulating cell-permeable dominant negative survivin (SR9) with locked nucleic acid (LNA) aptamers targeting EpCAM and nucleolin (termed as "nanobullets") in vitro (2D and 3D cell culture models) and in vivo (colon cancer mouse xenograft model). We incorporated three LNA modifications in each sequence in order to enhance the stability of these aptamers. Confocal microscopy revealed binding of the LNA-aptamers to their specific markers with high affinity. The muco-adhesive nanobullets showed 6-fold higher internalization in cancer cells when compared to non-cancerous cells, suggesting a tumour specific uptake. A higher intensity of nanobullets was observed in both the periphery and the core of the multicellular tumour spheroids compared to non-targeted CHNP-SR9. The nanobullets were found to be the highly effective as they led to a 2.26 fold (p < 0.05) reduction at 24 h and a 4.95 fold reduction (p ≤ 0.001) in the spheroid size at 72 h. The tumour regression was 4 fold higher in mice fed on a nanobullet diet when compared to a control diet. The nanobullets were able to show a significantly high apoptotic (p ≤ 0.0005) and necrotic index in the tumour cell population (p ≤ 0.005) when compared to void NPs. Therefore, our nanoparticles have shown highly promising results and therefore deliver a new conduit towards the approach of cancer-targeted nanodelivery. This journal is

Transporte electrogénico en el colon de ratas privadas de sodio : bloqueo de canales epiteliales versus inhibición de la NA, K-ATPASA

La privación dietaria de sodio estimula la secreción de aldosterona. En el colon de rata, la aldosterona elevada aumenta la absorción de Na+, pero además torna electrogénico el mecanismo de absorción (normalmente electroneutro). Dicho transporte electrogénico puede suprimirse mediante el bloqueo de los canales epiteliales de Na+ en la membrana apical o la inhibición de la Na, KATPasa de la membrana basolateral. La absorción electrogénica de sodio está estrechamente acoplada al metabolismo aerobio, pero se desconoce si el bloqueo de los canales de Na+ reduce el consumo de oxígeno en igual medida que la inhibición de la Na, K-ATPasa. Se obtuvieron preparados de mucosa aislada del colon distal de ratas alimentadas con una dieta hiposódica por 10 días. Se determinó simultáneamente la corriente de cortocircuito y el consumo de oxígeno en condición basal y luego del bloqueo de canales de Na+ con amilorida (n=12) o de la Na, K-ATPasa con uabaína (n=12). Ambos tratamientos redujeron la corriente de cortocircuito en igual medida (>80%), pero la reducción en el consumo de oxígeno fue mayor con uabaína que con amilorida (p<0.03). Esto se debe probablemente a que la Na, KATPasa cumple otras funciones, además del transporte transepitelial de Na+, que son suprimidas por la uabaína pero no por la amilorida.

Electrolyte transport in the mammalian colon: mechanisms and implications for disease Kunzelmann and Marcus Mall

Electrolyte Transport in the Mammalian Colon: Mechanisms and Implications for Disease. Physiol. Rev. 82: 245-289, 2002.The colonic epithelium has both absorptive and secretory functions. The transport is characterized by a net absorption of NaCl, short-chain fatty acids (SCFA), and water, allowing extrusion of a feces with very little water and salt content. In addition, the epithelium does secret mucus, bicarbonate, and KCl. Polarized distribution of transport proteins in both luminal and basolateral membranes enables efficient salt transport in both directions, probably even within an individual cell. Meanwhile, most of the participating transport proteins have been identified, and their function has been studied in detail. Absorption of NaCl is a rather steady process that is controlled by steroid hormones regulating the expression of epithelial Na+ channels (ENaC), the Na+-K+-ATPase, and additional modulating factors such as the serum- and glucocorticoid-regulated kinase SGK. Acute regulation of absorption may occur by a Na+ feedback mechanism and the cystic fibrosis transmembrane conductance regulator (CFTR). Cl- secretion in the adult colon relies on luminal CFTR, which is a cAMP-regulated Cl- channel and a regulator of other transport proteins. As a consequence, mutations in CFTR result in both impaired Cl- secretion and enhanced Na+ absorption in the colon of cystic fibrosis (CF) patients. Ca2+- and cAMP-activated basolateral K+ channels support both secretion and absorption of electrolytes and work in concert with additional regulatory proteins, which determine their functional and pharmacological profile. Knowledge of the mechanisms of electrolyte transport in the colon enables the development of new strategies for the treatment of CF and secretory diarrhea. It will also lead to a better understanding of the pathophysiological events during inflammatory bowel disease and development of colonic carcinoma.

Thermal Treatments of Fe—Mn Alkoxide of Glycerol: Infrared absorption and emission

Synthetic Fe—Mn alkoxide of glycerol samples are submitted to controlled heating conditions and examined by IR absorption spectroscopy. On the other hand, the same sample is studied by infrared emission spectroscopy (IRES), upon heating in situ from 100 to 600°C. The spectral techniques employed in this contribution, especially IRES, show that as a result of the thermal treatments ferromagnetic oxides (manganese ferrite) are formed between 350 and 400°C. Some further spectral changes are seen at higher temperatures.