Complete regression of local cancer using temperature-sensitive liposomes combined with ultrasound-mediated hyperthermia

Abstract

The development of treatment protocols that result in a complete response to chemotherapy has been hampered by free drug toxicity and the low bioavailability of nano-formulated drugs. Here, we explore the application of temperature-sensitive liposomes that have been formulated to enhance stability in circulation. We formed a pH-sensitive complex between doxorubicin (Dox) and copper (CuDox) in the core of lysolipid-containing temperature-sensitive liposomes (LTSLs). The complex remains associated at neutral pH but dissociates to free Dox in lower pH environments. The resulting CuDox-LTSLs were injected intravenously into a syngeneic murine breast cancer model (6 mg Dox/kg body weight) and intravascular release of the drug was triggered by ultrasound. The entire tumor was insonified for 5 min prior to drug administration and 20 min post drug injection. A single-dose administration of CuDox-LTSLs combined with insonation suppressed tumor growth. Moreover, after twice per week treatment over a period of 28 days, a complete response was achieved in which the NDL tumor cells and the tumor interstitium could no longer be detected. All mice treated with ultrasound combined with CuDox-LTSLs survived, and tumor was undetectable 8 months post treatment. Iron and copper-laden macrophages were observed at early time points following treatment with this temperature sensitive formulation. Systemic toxicity indicators, such as cardiac hypertrophy, leukopenia, and weight and hair loss were not detected with CuDox-LTSLs after the 28-day therapy.

Liposomes as nanomedical devices

“…ThermoDox liposomes can be triggered to release their payload by any heat-based treatment, such as radiofrequency thermal ablation, microwave hyperthermia, and high-intensity-focused ultrasound. 157 A complete regression of local cancer using temperaturesensitive liposomes combined with ultrasound-mediated hyperthermia was recently reported by Kheirolomoom et al 164 These authors employed temperature-sensitive liposomes containing lysolipid, loaded with a pH-sensitive complex formed by Dox and copper, ie, CuDox. The complex remains associated at neutral pH, but dissociates to give free Dox …”

“…Systemic toxicity indicators, such as cardiac hypertrophy, leukopenia, and weight and hair loss, were not detected with CuDox LTSLs after the 28-day therapy. 164 …”

Ultrasound ablation enhances drug accumulation and survival in mammary carcinoma models

“…Therefore, enhancing this effect is desirable. Alternatively, activatable nanotherapeutics release their cargo in response to changes in pH, temperature, or other stimuli (12). Temperature-sensitive liposomes (TSL) have been paired with ultrasound hyperthermia (34,35) and shown to increase drug accumulation in the insonified tumor.…”

“…This can be used to generate maps of thermal dose with the thermal isoeffect measure cumulative equivalent minutes at 43°C (CEM43) (11). As CEM43 increases rapidly with temperature, high temporal resolution is particularly important for ablative strategies that utilize high temperature and short heating time, but minimize toxicity to surrounding tissue (12). By modeling the thermal dose and comparing this to the experimental results, the effect of ablation on delivery can be assessed at microscopic and macroscopic scales both within and surrounding the ablated region.…”

GEM-loaded magnetic albumin nanospheres modified with cetuximab for simultaneous targeting, magnetic resonance imaging, and double-targeted thermochemotherapy of pancreatic cancer cells

“…Studies in recent years have showed that multimodal therapy always exhibits more effectiveness in tumor suppression than single-modality treatment. [39][40][41] Thermochemotherapy for tumor therapy has attracted further attention and been widely used throughout the world, achieving satisfactory therapeutic outcomes. 42 In our study, we found that with either the targeted or nontargeted approaches, thermochemotherapy brought more significant inhibition of growth and induction of apoptosis in AsPC-1 cells than their chemotherapy-alone counterparts.…”