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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. Graphical Abstract