OBJECTIVE: The effect of surface-modification of Tamoxifen (Tam)-loaded-niosomes on drug cytotoxicity and bio-distribution, via functionalization with chitosan and/or PEGylation, was investigated.
METHODS: Tam-loaded hybrid-nanocarriers (Tam-loaded niosomes, chitosomes, PEGylated niosomes, and PEGylated chitosomes) were formulated and characterized.
RESULTS: Chitosanization with/without PEGylation proved to selectively enhance Tam-release at the cancerous-acidic micromilieu. Cytotoxic activity study showed that Tam-loaded PEGylated niosomes had a lower IC50 value on MCF-7 cell line (0.39, 0.35, and 0.27 times) than Tam-loaded PEGylated chitosomes, Tam-loaded niosomes, and Tam-loaded chitosomes, respectively. Cell cycle analysis showed that PEGylation and/or Chitosanization significantly impact Tam efficiency in inducing apoptosis, with a preferential influence of PEGylation over chitosanization. The assay of Annexin-V/PI double staining revealed that chitosanized-nanocarriers had a significant role in increasing the incidence of apoptosis over necrosis. Besides, PEGylated-nanocarriers increased apoptosis, as well as total death and necrosis percentages more than what was shown from free Tam. Moreover, the average changes in both Bax/Bcl-2 ratio and Caspase 9 were best improved in cells treated by Tam-loaded PEGylated niosomes over all other formulations. The in-vivo study involving DMBA-induced-breast cancer rats revealed that PEGylation made the highest tumor-growth inhibition (84.9 %) and breast tumor selectivity, while chitosanization had a lower accumulation tendency in the blood (62.3 ng/ml) and liver tissues (103.67 ng/ml). The histopathological specimens from the group treated with Tam-loaded PEGylated niosomes showed the best improvement over other formulations.
CONCLUSIONS: All these results concluded the crucial effect of both PEGylation and chitosan-functionalization of Tam-loaded niosomes in enhancing effectiveness, targetability, and safety.

OBJECTIVE: According to the regulatory guidelines, one of the critical steps in using in-vitro permeability methods for permeability classification is to demonstrate the suitability of the method. Here, suitability of the permeability method by using a monolayer of cultured epithelial cells was verified with different criteria.
METHODS: Imaging with a transmission electron microscope was used for characterisation of the cells. Monolayer integrity was confirmed by transepithelial electrical resistance measurements and permeability of zero permeability marker compounds. Real-time polymerase chain reaction was employed to evaluate expression levels of 84 known transporters. Samples for bidirectional permeability determination were quantified by ultra-performance liquid chromatography.
RESULTS: The Caco-2 cells grow in an intact monolayer and morphologically resemble enterocytes. Genes of 84 known transporters were expressed at different levels; furthermore, expression was time depended. Functional expression of efflux transporter P-glycoprotein was confirmed. We established a correlation between permeability coefficients of 21 tested drug substances ranging from low, moderate and high absorption with human fraction absorbed literature data (R2  = 0.84).
CONCLUSIONS: Assay standardisation assures the consistency of experimental data. Only such fully characterised model has the ability to accurately predict drug\'s intestinal permeability at the early stage of research or for the BCS-based biowaiver application.

OBJECTIVE: It is challenging to deliver the therapeutic drug effectively to the posterior ocular disease location with optimized exposure and long-term effects when treating proliferative vitreoretinopathy (PVR). The objective of this study is to develop a novel biodegradable and long-acting ocular implant for PVR therapy with ligustrazine as the active ingredient.
METHODS: The ligustrazine implants were prepared with poly(DL-lactide-co-glycolide) using a hot-melting extrusion. The physicochemical properties of the implants were characterized. The effectiveness of the selected ligustrazine implants was evaluated in a PVR rabbit model. Furthermore, the in-vitro drug release profile and pharmacokinetics were compared, and in-vitro/in-vivo correlations were evaluated.
RESULTS: The optimal implants had an ideal zero-order in-vitro drug release profile, which was correlated with the in-vivo drug absorption fraction in the vitreous bodies of the rabbits. The sustained-release ligustrazine implants significantly reduced the development of PVR in the animal model.
CONCLUSIONS: Ligustrazine implants can be used to treat posterior ocular disease in rabbit animal models, and it provides more choices for medical research on posterior ocular disease.