Triggered doxorubicin release in solid tumors from thermosensitive liposome-peptide hybrids: Critical parameters and therapeutic efficacy

Abstract

Temperature-sensitive vesicles designed by inclusion of leucine zipper peptides within a lipid bilayer (Lp-Peptide hybrids) encapsulating Doxorubicin (DOX) have been reported. Intravenous administration of these constructs prolonged blood circulation kinetics and increased tumor accumulation in vivo with local mild hyperthermia. In this study, the biological activity of the DOX-loaded Lp-Peptide hybrid vesicles was further investigated at the cellular level and in vivo compared to lysolipidcontaining temperature-sensitive liposomes (LTSL) and traditional temperature-sensitive liposomes. Lp-Peptide vesicles were not toxic to cell cultures at 37 C, while effective cancer cell toxicity was observed after 1 hr of heating at 42 C. The activity of Lp-Peptide vesicles in vivo was studied using two different heating protocols to obtain tumor intravascular or interstitial drug release. Lp-Peptide vesicle treatment allowing intravascular DOX release showed equally effective tumor growth retardation and survival to that of LTSL treatment. The Lp-Peptide vesicles also offered therapeutic responses using the alternative heating protocol to maximise drug release within the tumor interstitium. Matching the drug release kinetics of temperaturesensitive vesicles with the heating protocol applied is considered the most critical factor to determine therapeutic efficacy in the clinical translation of such modalities.The design of drug delivery technologies with controllable drug retention and drug release properties is a challenge. Despite a decrease in the risk of drug-associated toxicity 1 and delivering more drug to the tumor tissue by encapsulation inside long-circulating liposomes, 2 the therapeutic efficacy of liposomal Doxorubicin (DOX) is not dramatically enhanced because of limited drug release from liposomes. 3-5 Local hyperthermia 6 represents one external trigger that can improve liposomal drug release by increasing their extravasation into the tumor, 7 triggering content release 8 and potentiating a chemotherapeutic effect. 9 Different temperature-sensitive liposomes (TSL) have been developed following the original work by Yatvin and Weinstein. 10,11 This "traditional" TSL system has since been further developed for increased blood circulation half-life 12,13 and serum stability. 14,15 In addition drug release kinetics at the lipid bilayer phase transition temperature have been enhanced by inclusion of additional lipid components, such as lysolipids or oligoglycerol. [16][17][18] The ultrafast drug release capabilities of some TSL offer a new paradigm in liposomal DOX release compared to nontemperature-sensitive liposomes (NTSL), such as the clinically used Doxil V R . Previous studies suggested that ultrafast drug release within the tumor vasculature should be achieved upon reaching the heated tumor tissue if TSL were injected just prior to or during HT. 19 This type of drug release is termed "intravascular" release approach and its main advantage is that DOX-loaded liposomes do not need to extravasate from the vascul...

Selective Liposomal Transport Through Blood Brain Barrier Disruption in Ischaemic Stroke Reveals Two Distinct Therapeutic Opportunities

“…Organic solvents were then evaporated to produce the lipid film. [64][65][66] Lipid films were kept protected from light and hydration was performed with HBS (20mM HEPES, 150mM NaCl, pH 7.4) to a final lipid concentration of 12.5mM. To produce small unilamellar liposomes, the size was reduced by extrusion though 800nm and 200nm polycarbonate filters 5 times each then 20-40 times through 100nm membranes using a mini-Extruder (Avanti Polar Lipids, Alabaster, AL).…”

Design strategies for physical-stimuli-responsive programmable nanotherapeutics

“…Hybrids of different thermoresponsive polymers and or polypeptides into a nanomaterial system can have synergetic effects on the temperature-responsiveness and consequently better therapeutic effects of the nanosystem. For example, a hybrid nanosystem containing the thermoresponsive amphiphilic leucine zipper peptide and thermoresponsive liposomes (Figure 1B), which have a phase transition temperature 42 °C, prolonged the blood circulation time of the loaded doxorubicin, leading to a 3-fold accumulation of the drug in the heated tumor site in SW480 tumor-bearing mice in comparison to lysolipid-modified thermoresponsive liposomes [71,83]. …”

“…Various materials such as polymers, mesoporous silica, squalenoyl-gemcitabine [83], and lipids have been used to form the shell of the magnetic field-responsive nanomaterials [114]. Superparamagnetic iron oxide nanoparticles (SPIONs) are the predominantly studied magnetic field-responsive nanomaterials because they can be guided to the target site without retaining any residual magnetism, which is attributed to quantum effects at the nanometer scale.…”

Strategies for improving the intratumoral distribution of liposomal drugs in cancer therapy

“…Some of the reasons have been premature release of the drug from the liposome at normal body temperatures before reaching the tumor target. Another problem has been low intratumoral penetration of the drug released from the liposome because of redistribution in the circulation following intravascular release [3, 71–73]. Currently, several strategies are being investigated to improve liposome-based hyperthermia [25, 26].…”

“…Currently, several strategies are being investigated to improve liposome-based hyperthermia [25, 26]. These approaches include utilizing newer pegylated thermosensitive liposome and leucine zipper peptide-lipid hybrid formulations with improved in vivo drug retention and increased doxorubicin bioavailability in tumors [71, 73]. Two-step hyperthermia protocols have been described in which the first temperature step increases extravasation and intratumoral penetration of longer circulating thermosensitive liposome formulations and a second heating step increases intratumoral drug release [74].…”