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

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.

Download the full article as a PDF here or read it here

Materials: Enoxaparin (Enox, average MW 4500 Da) was purchased from Sanofi-Aventis GmbH (Wien, Austria). PeceolTM (glyceryl monooleate) and Labrafil® M 1944 (oleoyl polyoxyl-6 glycerides) were a gift from Gattefossé (Saint-Priest, France). Palmitoyl chloride (PC), Cremophor EL (polyoxyl-35 castor oil), propylene glycol (PG), Fe (III) chloride, L-cysteine ethyl ester hydrochloride, toluidine blue, sodium chloride (NaCl), Triton X-100, fluorescein diacetate (FDA), sodium hydroxide (NaOH), and tetrahydrofuran (THF) were obtained from Sigma-Aldrich Co. (Vienna, Austria). Docetaxel (DTX) was purchased by Enzo Life (Farmingdale, NY, USA), and sodium chloride, calcium chloride, sodium phosphate dibasic, potassium chloride, and bovine serum albumin (BSA) were obtained from Sigma-Aldrich Co. (Milan, Italy). Human plasma was obtained from healthy volunteers. All solvents, chemicals, and media were of analytical grade and used as received. Breast cancer MCF7, SKBR3, T74D, and MDA-MB-231 cells, and human non-small cell lung cancer (NSCLC) NCI-H1395, NCI-H1650, NCI-H1975, and A549 were provided from ATCC (Manassas, VA, USA), cultured in their respective media containing fetal bovine serum (10% v/v), penicillin-streptomycin (1% v/v), and L-glutamine (1% v/v). The non-targeting siRNA sequence (Trilencer-27 Universal scrambled negative control siRNA duplex, #R30004), the FGFR1-targeting siRNAs pool of 3 unique 27mer siRNA duplexes (#SR320159), the CRISPR pCas vectors targeting MRP1 (#KN418182), BCRP (#KN405640), or the non-targeting vector (#GE100003) were purchased from Origene (Rockville, MD, USA). Anti-FGFR1 antibody (#ab58516) and anti-MRP1/ABCC1 (#ab24102) were purchased from Abcam (Cambridge, UK), while the anti-Pgp/ABCB1 (15D3) and the anti-BCRP/ABCG2 (B1) were purchased from BD Biosciences (San Josè, CA, USA) and Santa Cruz Biotechnology Inc. (Santa Cruz, CA, USA), respectively. The anti-β-tubulin (D10) was also purchased from Santa Cruz Biotechnology Inc. and the secondary horseradish peroxidase-conjugated antibodies were obtained from Bio-Rad Laboratories (Hercules, CA, USA). Ki67 (AB9260) was purchased from Sigma Aldrich (Milan, Italy) while the peroxidase-conjugated secondary antibody was obtained from Dako (Glostrup, Denmark).

Article information: Campani, V.; Salaroglio, I.C.; Nele, V.; Kopecka, J.; Bernkop-Schnürch, A.; Riganti, C.; De Rosa, G. Targeted Self-Emulsifying Drug Delivery Systems to Restore Docetaxel Sensitivity in Resistant Tumors. Pharmaceutics 2022, 14, 292. https://doi.org/10.3390/pharmaceutics14020292