Nanostructured lipid carriers loaded with tributyrin as an alternative to improve anticancer activity ofall-transretinoic acid

Abstract

Objectives All-trans retinoic acid (ATRA) is one of the most successful examples of differentiation agents and histone deacetylase inhibitors, such as tributyrin (TB), are known for their antitumor activity and potentiating action of drugs such as ATRA. Nanostructured lipid carriers (NLC) represent a promising alternative to the encapsulation of lipophilic drugs such as ATRA. This study aimed to develop, characterize, and evaluate the cytotoxicity of ATRA-TB-loaded nanostructured lipid carriers (NLC) for cancer treatment. Methods The influence of in situ formation of an ion pairing between ATRA and a lipophilic amine (benethamine; BNT) on the characteristics of NLC (size, zeta potential, encapsulation efficiency) was evaluated. Tributyrin (TB), a butyric acid donor, was used as a component of the lipid matrix. In vitro activity on cell viability and distribution of cell cycle phases were evaluated for MCF-7, MDA-MB-231, HL-60, and Jurkat cell lines. Results The presence of the amine significantly increased the encapsulation efficiency of ATRA in NLC. Inhibition of cell viability by TB-ATRA-loaded NLC was more pronounced than the free drug. Analysis of the distribution of cell cycle phases also showed increased activity for TB-ATRA-loaded NLC, with the clear effect of cell cycle arrest in G0/G1 phase transition. The presence of TB played an important role in the activity of the formulation. Conclusion Taken together, these findings suggest that TB-ATRA-loaded NLC represent a promising alternative to intravenous administration of ATRA in cancer treatment.

Hyaluronic acid-coated nanoemulsions loaded with a hydrophobic ion pair of all-trans retinoic acid for improving the anticancer activity

“…The presence of insoluble ATRA crystals in the external aqueous phase of ATRA-NE and HA-ATRA-NE was evaluated by polarized light microscopy in order to confirm the high EE. The obtained images are also shown in Figure 2, revealing that there were no ATRA crystals in the AP of both formulations, as expected (Carneiro et al, 2012;Silva et al, 2015;Silva et al, 2016).…”

“…As expected, high EE (96.7 ± 4.9%) was obtained, which is in good agreement with our previous work involving incorporation of HIP between ATRA and lipophilic amines in lipid nanocarriers. ATRA concentration in the AP was found to be negligible as previously reported (Carneiro et al, 2012;Da Silva et al, 2015;Silva et al, 2015;Silva et al, 2016). The high ATRA retention in lipid matrix is related to the hydrophobicity of the counterion used in the HIP strategy, while the lipophilic amine is associated with intense interaction of ATRA with the lipid matrix (Oliveira et al, 2017).…”

“…All these factors have limited the clinical use of both oral and intravenous ATRA formulations. An alternative to enabling the development of intravenous formulations has been the incorporation of ATRA in lipid nanostructured systems such as nanoemulsions (NE), solid lipid nanoparticles (SLN), nanostructured lipid carriers, or liposomes (Hwang et al, 2004;Lim, Lee, Kim 2004;Chansri et al, 2006; Page 2 / 10 Kawakami et al, 2006;Carneiro et al, 2012;Silva et al, 2015).…”

“…Despite its lipophilicity, encapsulation of ATRA in lipid systems such as SLN is usually low (Jenning, Gohla, 2001) unless a high surfactant/lipid ratio is used (Lim, Kim, 2002;Hu, Tang, Cui 2004). Our group has previously reported that the in situ formation of hydrophobic ion pairs (HIP) of ATRA and lipophilic amines such as stearylamine (SA), benethamine, and maprotiline can significantly increase the ATRA incorporation within the lipid matrix (Castro et al, 2009;Carneiro et al, 2012;Silva et al, 2015;Silva et al, 2016).…”

Validation of a Chromatographic Analytical Method for Quantification of Benznidazole Incorporated in Nanostructured Lipid Formulations

“…21 In this case, the OP comprised of solid-liquid lipid matrix of Crodamol ® and Compritol ® , and the AP were heated to 85 °C separately. Next, the AP was added drop by drop to the OP with a constant manual agitation.…”