Abstract
1076
Objectives: Photothermal therapy (PTT) is an effective anti-cancer therapeutic strategy, which utilizes photoabsorbers to generate hyperthermia to kill cancer cells under a laser irradiation. Recently, gold (Au) coated liposomes were reported to have a PTT effect, a good excretory property and a high biocompatibility. However, the Au coated liposomes have drawbacks such as its low stability in vivo and limited ability for further functionalization. Herein, we developed a theranostic multilayered nanomaterial by adding an additional liposomal layer to the Au coated liposome. The additional liposomal layer enabled further functionalization: 1) radiolabeling for in vivo imaging and 2) adding PEG groups to enhance in vivo stability.
Methods: After an inner liposome was prepared by a thin film hydration method, Au layer was coated by Au seed solution. The Au coated liposome (AL) was covered by an additional liposomal layer (LAL) by the same process as inner liposome prepared using the AL solution as the lipid hydrating solution instead of deionized water (DW). Sizes of prepared AL and LAL in DW, phosphate-buffered saline (PBS) and cell media were characterized by a dynamic light scattering (DLS) for the stability tests. After measuring absorbance of AL and LAL, photothermal effect was demonstrated using the 808 nm laser, then in vitro PTT was conducted with 4T1 breast cancer cell line. LAL was radiolabeled with 64Cu (64Cu-LAL) and in vivo positron emission tomography (PET) was performed after intravenous injection of 64Cu-LAL to the 4T1 orthotopic mouse model. In vivo PTT was conducted using AL and LAL under the 808 nm laser irradiation. Overall schematic diagram was shown in Scheme 1.
Results: The hydrodynamic size of LAL was 63±22 nm and the high absorbance bands at 700-900 nm were observed in both AL and LAL, which is suitable for the 808 nm laser. According to the DLS data, LAL showed a high stability in the physiological conditions up to 14 days while AL was destabilized within 1 hour. AL and LAL with the same Au concentration showed a similar photothermal effect (~42℃) under the laser irradiation (S1b). Photothermal effect was maintained in both AL and LAL up to 4 cycles of laser irradiation (S1c). Both AL and LAL had no significant cytotoxicity up to 11.85 mg/mL of Au without laser, however under the laser irradiation, LAL demonstrated significantly higher cytotoxicity than AL from 0.47 to 4.74 mg/mL of Au (S1d, e). The radiolabeling efficiency of 64Cu-LAL was 94% and the radiochemical stability was 88% up to 24 hours in PBS (S2b). In vivo PET images showed that 64Cu-LAL had a good blood circulation property with 8.03 hours of circulation half-life and had a considerable tumor uptake up to ~16%ID/g 24 hours after the injection (S2a, c, d). Tumor to heart/liver/muscle ratios were 1.4, 0.8, and 23, respectively, 24 hours after the injection (S2e, f, g). In vivo PTT experiment was conducted as shown in Scheme 2. We found that the increased tumor temperature under the laser irradiation in the 4T1 tumor bearing mice injected LAL as well as AL, however the temperature changes were higher in LAL injected mice than in AL injected mice. In vivo PTT demonstrated that LAL injected and laser-irradiated group (LAL_laser) showed successful tumor growth suppression, while other groups (AL_laser, NS_laser, LAL_w/o laser, AL_w/o laser) did not show anti-tumor effect (S3a, b).
Conclusions: We developed LAL that has an excellent stability and additional imaging ability by radiolabeling compare to AL. LAL showed a high blood circulation and effective tumor targeting abilities revealed by in vivo PET imaging of 64Cu-LAL. In vivo PTT result demonstrated that the combination of intravenous injection of LAL and laser irradiation was able to suppress the tumor progression in 4T1 orthotopic tumor mouse model. Based on the high stability, tumor targeting efficiency and imaging ability, LAL could be a promising theranostic PTT agent effective for metastatic lesions.
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