Abstract
The therapeutic effectiveness of chemotherapy is optimal only when tumor cells have maximum drug exposure. A thermoresponsive liposomal formulation (ThermoDox; Lysolipid liposomes) rapidly releases DOX in regions where local tissue temperatures are elevated to at least 40 °C. Although Lysolipid liposomes have considerable therapeutic potential, roughly 50% of encapsulated DOX is released within 1 h in physiological environments. Lysolipid dissociation from liposomes, which is mediated by plasma proteins, is a highly likely cause of their intravenous instability. Thus, in study I, a thermoresponsive bubble-generating liposomal system that does not contain lysolipids was evaluated for its ability to trigger localized extracellular drug delivery. The key component in this liposomal formulation is encapsulated ammonium bicarbonate (ABC), which creates the transmembrane gradient needed for highly efficient DOX encapsulation. At an elevated temperature of 42 °C, ABC decomposition generates CO2 bubbles, creating permeable defects in the lipid bilayer that rapidly releases DOX and instantly increases the drug concentration locally. Because the generated CO2 bubbles are hyperechogenic, they also enhance ultrasound imaging results. Consequently, this novel liposomal system encapsulated with ABC may be able to monitor a temperature-controlled drug delivery process. Study II examined the feasibility of using this thermoresponsive bubble-generating liposomal system (ABC liposomes) for tumor-specific chemotherapy under mild hyperthermia. Incubation of ABC liposomes with rat whole blood resulted in a significantly smaller decrease in the retention of encapsulated DOX than that by Lysolipid liposomes, indicating superior plasma stability. Biodistribution study results demonstrate that the ABC formulation circulated longer than its Lysolipid counterpart. After the ABC liposome suspension was injected into mice with tumors that were heated locally, decomposition of the ABC encapsulated in liposomes facilitated immediate thermal activation for CO2 bubble generation, leading to increased intratumoral DOX accumulation. Consequently, the antitumor efficacy of ABC liposomes was superior to that of their Lysolipid counterparts. These analytical results indicate that this thermoresponsive bubble-generating liposomal system is a promising local drug delivery system activated at hyperthermia temperatures for tumor-specific chemotherapy. Since nonspecific distribution of therapeutic agents and nontargeted heating frequently cause undesirable side effects during cancer treatment, study III describes a novel liposomal system that can deliver both heat and a therapeutic agent, DOX, simultaneously into targeted tumor cells to exert its cytotoxicity intracellularly. A hybridized Mucin-1 aptamer was conjugated on the surface of test liposomes, which can function as a recognition probe to enhance their cell uptake, as well as a molecular beacon to signal when the internalized particles were maximized. Additionally, gold nanocages encapsulated in liposomes effectively converted near-infrared light irradiation into localized heat to directly damage cancerous cells and thermally trigger a high DOX release to reach the therapeutic threshold instantly. This combined treatment can significantly increase the drug potency, making it a promising approach for cancer therapy.