Ultrasonically controlled estrone-modified liposomes for estrogen-positive breast cancer therapy

Abstract

A new modality of drug targeting to tumors has been proposed. The ligand-mediated approach, that already increases the therapeutic index of the drug, can still be optimized by the encapsulation of the drug into sonosensitive nanoparticles. In this work, an endogenous ligand, estrone, was used to synthesize doxorubicin-encapsulating liposomes for estrogen receptor (ER)-positive breast cancer therapy with cyanuric chloride (2,4,6 trichloro-1,3,5 triazine) being used as a linking molecule to attach 3-OH group of estrone to the surface of liposomes. Then, drug release from liposomes was studied using ultrasound waves as a triggering mechanism with different frequencies and power densities. In addition, drug uptake by two cell lines ER-positive (MCF-7) and ER-negative (MDA-MB-231) was assessed, with the former cell line being examined later to study the synergetic effect of the receptor mediator targeting and ultrasound trigger. The sizes of the liposomes loaded with calcein (as a doxorubicin model drug) were determined by dynamic light scattering, and they were characterized as large unilamellar vesicles (LUVs). The release from the prepared liposomes triggered by ultrasound (US) waves at low frequency (20 kHz) and high frequency (1.07 and 3.24 MHz), at several power densities, was determined by monitoring the changes in calcein fluorescence, using a spectrofluorometer. Increasing power densities showed a significant effect on release at high frequencies and during the first two US pulses at low frequency. The echogenicity of the liposomes was proven and characterized at different power densities and frequencies. To confirm the viability of the carrier as a doxorubicin carrier, doxorubicin-encapsulating liposomes were prepared using the ammonium sulfate transmembrane gradient method. The liposomes were LUVs and were US-sensitive, exhibiting similar behavior to calcein-encapsulating liposomes. The calcein uptake by an ER + cell line (MCF-7) was compared with the uptake by an ER-cell line (MDA-MB-231). The MCF-7 uptake was significantly higher than the MDA-MB-231 uptake, which proved the targeting potential of estrone-conjugated liposomes. The exposure to low-frequency ultrasound (LFUS) revealed a statistically significant uptake of calcein compared to uptake without ultrasound. The described drug delivery (DD) system, comprising a new echogenic liposomal formulation, promises a non-immunogenic and site-specific biomedical approach to ER-positive breast cancer therapy.

NLRP3 inflammasome inactivation driven by miR‑223‑3p reduces tumor growth and increases anticancer immunity in breast cancer

“…However, the present study presents certain limitations, due to the fact that MDA-MB231, MCF-7 and SKBR3 are three different subtypes of breast cancer cell lines. MCF-7 is estrogen receptor (ER)- and progesterone receptor (PR)-positive (22,23), and SKBR3 is human epidermal growth factor receptor 2 (HER2)-positive, whereas, MDA-MB231 is ER-, PR- and HER2-negative (24,25). Considering the limitations of the present study, further studies are required to investigate the role of the miR223-NLRP3 axis in MDA-MB231 and SKBR3 cells.…”

Targeted Delivery to Tumors: Multidirectional Strategies to Improve Treatment Efficiency

“…A comprehensive review on liposomal antitumor formulations is provided elsewhere [55,56]. The further directions in antitumor liposomal formulations progress are the development and improvement of stimuli-sensitive smart liposomes (thermo-, redox-, ultrasound-, enzyme-sensitive), magnetic liposomes, and liposomes for photodynamic therapy [57,58,59,60,61,62,63].…”

RGD peptide-mediated liposomal curcumin targeted delivery to breast cancer cells

“…19 Grafting liposomes with a variety of targeting ligands [e.g. hormones, 20 antibodies, 21 peptides, 22 aptamers 23 ] has proved successful in enhancing their specificity and targeting efficiency.…”