Modeling of the In Vitro Release Kinetics of Sonosensitive Targeted Liposomes.

Targeted liposomes triggered by ultrasound are a promising drug delivery system as they potentially improve the clinical outcomes of chemotherapy while reducing associated side effects. In this work, a comprehensive model fitting was performed for a large dataset of liposomal release profiles with seven targeting moieties (albumin, cRGD, estrone, hyaluronic acid, Herceptin, lactobionic acid, and transferrin) in addition to the control liposomes under ultrasound release protocols. Two levels of ultrasound frequencies were tested: low frequency (20 kHz) at 6.2, 9, and 10 mW/cm2 as well as high frequencies (1.07 MHz and 3 MHz) at 10.5 and 173 W/cm2. At a low frequency, Hixson-Crowell, Korsmeyer-Peppas, Gompertz, Weibull, and Lu-Hagen showed good fits to our release profiles at all three power densities. At high frequencies, the former three models reflected the best fit. These models will aid in predicting drug release profiles for future in vitro studies.

Photo-Induced Drug Release from Polymeric Micelles and Liposomes: Phototriggering Mechanisms in Drug Delivery Systems.

Chemotherapeutic drugs are highly effective in treating cancer. However, the side effects associated with this treatment lower the quality of life of cancer patients. Smart nanocarriers are able to encapsulate these drugs to deliver them to tumors while reducing their contact with the healthy cells and the subsequent side effects. Upon reaching their target, the release of the encapsulated drugs should be carefully controlled to achieve therapeutic levels at the required time. Light is one of the promising triggering mechanisms used as external stimuli to trigger drug release from the light-responsive nanocarriers. Photo-induced drug release can be achieved at a wide range of wavelengths: UV, visible, and NIR depending on many factors. In this review, photo-induced release mechanisms were summarized, focusing on liposomes and micelles. In general, light-triggering mechanisms are based on one of the following: changing the hydrophobicity of a nanocarrier constituent(s) to make it more soluble, introducing local defects within a nanocarrier (by conformational transformation or photo-cleavage of its lipids/polymers chains) to make it more porous or concentrating heat for thermo-sensitive nanocarriers to release their payload. Several research studies were also presented to explore the potentials and limitations of this promising drug release triggering mechanism.

Liposomes in Active, Passive and Acoustically-Triggered Drug Delivery.

Cancer has become one of the most deadly noncommunicable diseases globally. Several modalities used to treat cancer patients exist today yet many have failed to prove high efficacy with low side effects. The most common example of such modalities is the use of chemotherapeutic drugs to treat cancerous cells and deter their uncontrolled proliferation. In addition to the destruction of cancerous tissues, chemotherapy destroys healthy tissues as it lacks the specificity to annihilate cancerous cells only and preferentially, which result in adverse side effects including nausea, hair fall and myocardial infarction. To prevent the side effects of non-selective chemotherapy, cancer therapy research has been focused on the implementation of nanocarrier systems that act as vehicles to encapsulate drugs and selectively transport their agent to the tumor site. In this paper, we shed light on liposomes along with three anticancer drug delivery approaches: passive, active and ultrasound-triggered drug delivery.

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

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.