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Targeted Self-Emulsifying Drug Delivery Systems to Restore Docetaxel Sensitivity in Resistant Tumors.

ABSTRACT: The use of chemotherapeutic agents such as docetaxel (DTX) in anticancer therapy is often correlated to side effects and the occurrence of drug resistance, which substantially impair the efficacy of the drug. Here, we demonstrate that self-emulsifying drug delivery systems (SEDDS) coated with enoxaparin (Enox) are a promising strategy to deliver DTX in resistant tumors. DTX partition studies between the SEDDS pre-concentrate and the release medium (water) suggest that the drug is well retained within the SEDDS upon dilution in the release medium. All SEDDS formulations show droplets with a mean diameter between 110 and 145 nm following dilution in saline and negligible hemolytic activity; the droplet size remains unchanged upon sterilization. Enox-coated SEDDS containing DTX exhibit an enhanced inhibition of cell growth compared to the control on cells of different solid tumors characterized by high levels of FGFR, which is due to an increased DTX internalization mediated by Enox. Moreover, only Enox-coated SEDDS are able to restore the sensitivity to DTX in resistant cells expressing MRP1 and BCRP by inhibiting the activity of these two main efflux transporters for DTX. The efficacy and safety of these formulations is also confirmed in vivo in resistant non-small cell lung cancer xenografts.

SUBMITTER: Campani V

PROVIDER: S-EPMC8876228 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Targeted Self-Emulsifying Drug Delivery Systems to Restore Docetaxel Sensitivity in Resistant Tumors.

Campani Virginia V Salaroglio Iris Chiara IC Nele Valeria V Kopecka Joanna J Bernkop-Schnürch Andreas A Riganti Chiara C De Rosa Giuseppe G

Pharmaceutics 20220126 2

The use of chemotherapeutic agents such as docetaxel (DTX) in anticancer therapy is often correlated to side effects and the occurrence of drug resistance, which substantially impair the efficacy of the drug. Here, we demonstrate that self-emulsifying drug delivery systems (SEDDS) coated with enoxaparin (Enox) are a promising strategy to deliver DTX in resistant tumors. DTX partition studies between the SEDDS pre-concentrate and the release medium (water) suggest that the drug is well retained w ...[more]

PMID: 35214025

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Project description:Background: Sirtuin-1 (SIRT1), a histone deacetylase enzyme expressed in ocular tissues with intracellular localization, plays a critical protective role against various degenerative ocular diseases. The link between reduced SIRT1 levels and diabetic retinopathy (DR) has prompted the exploration of natural therapeutic compounds that act as SIRT1 agonists. Curcumin (CUR), which has been shown to upregulate SIRT1 expression, is one such promising compound. However, effective delivery of CUR to the deeper ocular tissues, particularly the retina, remains a challenge due to its poor solubility and limited ocular penetration following topical administration. Within this context, the development of self-nanoemulsifying drug delivery systems (SNEDDS) for CUR topical ocular delivery represents a novel approach. Methods: In accordance with our prior research, optimized SNEDDS loaded with CUR were developed and characterized post-reconstitution with simulated tear fluid (STF) at a 1:10 ratio, showing suitable physicochemical and technological parameters for ocular delivery. Results: An entrapment efficiency (EE%) of approximately 99% and an absence of drug precipitation were noticed upon resuspension with STF. CUR-SNEDDS resulted in a better stability and release profile than free CUR under simulated ocular conditions. In vitro analysis of mucoadhesive properties revealed that CUR-SNEDDS, modified with a cationic lipid, demonstrated enhanced interactions with mucin, indicating the potential for improved ocular retention. Cytotoxicity tests demonstrated that CUR-SNEDDS did not affect the viability of human corneal epithelial (HCE) cells up to concentrations of 3 μM and displayed superior antioxidant activity compared to free CUR in an oxidative stress model using retinal pigment epithelial (ARPE-19) cells exposed to hydroquinone (HQ). Cell uptake studies confirmed an enhanced accumulation of CUR within the retinal cells following exposure to CUR-SNEDDS compared to neat CUR. CUR-SNEDDS, at lower concentrations, were found to effectively induce SIRT1 expression. Conclusions: The cytocompatibility, antioxidant properties, and enhanced cellular uptake suggest that these developed systems hold promise as formulations for the delivery of CUR to the retina.

Project description:Neratinib maleate (NM), a tyrosine kinase inhibitor, is used in the treatment of breast cancer. NM is orally administered at a high dose of 290 mg due to its low solubility and poor dissolution rate at pH > 3, as well as gut-wall metabolism limiting its bioavailability. Self-emulsifying drug delivery systems (SEDDSs) of NM were developed in the current study to improve its oral bioavailability. The oily vehicle (clove oil) was selected based on the solubility of NM, while the surfactant and the cosurfactant were selected based on the turbidimetric analysis. Three different sets were screened for surfactant selection in the preparation of SEDDS formulations, the first set containing Cremophor® EL alone as the surfactant, the second set containing a mixture of Cremophor® EL (surfactant) and Caproyl® PGMC (cosurfactant), and the third set containing a mixture of Cremophor® EL (surfactant) and Capmul® MCM C8 (cosurfactant). Propylene glycol was used as the cosolubilizer in the preparation of SEDDSs. A series of studies, including the construction of ternary phase diagrams to determine the zone of emulsification, thermodynamic stability studies (involving dilution studies, freeze-thaw, and heating-cooling studies), turbidimetric analysis, and physicochemical characterization studies were conducted to identify the two most stable combinations of SEDDSs. The two optimized SEDDS formulations, TP16 and TP25, consisted of clove oil (45% w/w) and propylene glycol (5% w/w) in common but differed with respect to the surfactant or surfactant mixture in the formulations. TP16 was prepared using a mixture of Cremophor® EL (surfactant) and Caproyl® PGMC (cosurfactant) in a 4:1 ratio (50% w/w), while TP25 contained only Cremophor® EL (50% w/w). The mean globule sizes were 239.8 ± 77.8 nm and 204.8 ± 2.4 nm for TP16 and TP25, respectively, with an emulsification time of <12 s for both formulations. In vitro drug dissolution studies performed at different pH conditions (3.0, 4.5, 6.8) have confirmed the increase in solubility and dissolution rate of the drug by TP16 and TP25 at all pH conditions compared to plain NM. An oral pharmacokinetic study in female Wistar rats showed that the relative bioavailability (Frel) values of TP16 and TP25 over the plain NM were 2.18 (p < 0.05) and 2.24 (p < 0.01), respectively.

Dataset Information

Targeted Self-Emulsifying Drug Delivery Systems to Restore Docetaxel Sensitivity in Resistant Tumors.

Publications

Targeted Self-Emulsifying Drug Delivery Systems to Restore Docetaxel Sensitivity in Resistant Tumors.

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