MRI Monitoring of Tumor-Selective Anticancer Drug Delivery with Stable Thermosensitive Liposomes Triggered by High-Intensity Focused Ultrasound.

Monitoring of drug release from a heat-activated liposome carrier provides an opportunity for real-time control of drug delivery and allows prediction of the therapeutic effect. We have developed short-chain elastin-like polypeptide-incorporating thermosensitive liposomes (STLs). Here, we report the development of STL encapsulating gadobenate dimeglumine (Gd-BOPTA), a MRI contrast agent, and doxorubicin (Dox) (Gd-Dox-STL). The Dox release profile from Gd-Dox-STL was comparable to Gd-Dox-LTSL; however, the serum stability of Gd-Dox-STL was much higher than Gd-Dox-LTSL. MRI studies showed that the difference in T1 relaxation time between 37 and 42 °C for Gd-Dox-STL was larger than the difference for Gd-Dox-LTSL. Although relaxivity for both liposomes at 42 °C was similar, the relaxivity of Gd-Dox-STL at 37 °C was 2.5-fold lower than that of Gd-Dox-LTSL. This was likely due to Gd-BOPTA leakage from the LTSL because of low stability at 37 °C. Pharmacokinetic studies showed plasma half-lives of 4.85 and 1.95 h for Gd-Dox-STL and Gd-Dox-LTSL, respectively, consistent with in vitro stability data. In vivo MRI experiments demonstrated corelease of Dox and Gd-BOPTA from STL under mild hyperthermia induced by high-intensity focused ultrasound (HIFU), which suggests STL is a promising tumor selective formulation when coupled with MR-guided HIFU.

Gas-filled phospholipid nanoparticles conjugated with gadolinium play a role as a potential theragnostics for MR-guided HIFU ablation.

To develop a long-circulating theragnostics, meaning therapeutics and diagnostics for MR-guided HIFU ablation, we designed and prepared Gd-C(5)F(12)-phospholipid nanobubbles (PLNs) 30-100 nm in diameter. The biochemical and physical characterization of Gd-C(5)F(12)-PLNs were performed. Since Gd-C(5)F(12)-PLN-50 (Φ = 50 nm) and Gd-C(5)F(12)-PLN-100 (Φ = 100 nm) enhanced the hyperthermal effect of HIFU size- and concentration-dependently in a tissue-mimicking phantom, its circulation, distribution, tumor accumulation and tumor ablation were examined in tumor-bearing mice. The plasma-half life of Gd-C(5)F(12)-PLNs was longer than 1.5 hrs. Gd-C(5)F(12)-PLNs mainly accumulated in the liver and the spleen, suggesting that they are slowly secreted through the hepatobiliary pathway. Monitored by the T1 signal intensity of MR, Gd-C(5)F(12)-PLNs accumulated in tumor tissues for 8 hours in mice. HIFU with Gd-C(5)F(12)-PLN-100 showed the increased tumor ablation area as compared with HIFU alone. The results suggest that Gd-C(5)F(12)-PLNs exhibit a potential theragnostics for MR-guided HIFU ablation.