Microwave Responsive Nanoplatform via P-Selectin Mediated Drug Delivery for Treatment of Hepatocellular Carcinoma with Distant Metastasis.

Hepatocellular carcinoma (HCC) with metastatic disease is associated with a low survival in clinical practice. Many curative options including liver resection, transplantation, and thermal ablation are effective in local but limited for patients with distant metastasis. In this study, the efficacy, specificity, and safety of P-selectin targeted delivery and microwave (MW) responsive drug release is investigated for development of HCC therapy. By encapsulating doxorubicin (DOX) and MW sensitizer (1-butyl-3-methylimidazolium-l-lactate, BML) into fucoidan conjugated liposomal nanoparticles (TBP@DOX), specific accumulation and prominent release of DOX in orthotopic HCC and lung metastasis are achieved with adjuvant MW exposure. This results in orthotopic HCC growth inhibition that is not only 1.95-fold higher than found for nontargeted BP@DOX and 1.6-fold higher than nonstimuli responsive TP@DOX but is also equivalent to treatment with free DOX at a 10-fold higher dose. Furthermore, the optimum anticancer efficacy against distant lung metastasis and effective prevention of widespread dissemination with a prolonged survival is described. In addition, no adverse metabolic events are identified using the TBP@DOX nanodelivery system despite these events being commonly observed with traditional DOX chemotherapy. Therefore, administering TBP@DOX with MW exposure could potentially enhance the therapeutic efficacy of thermal-chemotherapy of HCC, especially those in the advanced stages.

Amplified intracellular Ca2+ for synergistic anti-tumor therapy of microwave ablation and chemotherapy.

BACKGROUND: Developing new strategies to reduce the output power of microwave (MW) ablation while keeping anti-tumor effect are highly desirable for the simultaneous achievement of effective tumor killing and avoidance of complications. We find that mild MW irradiation can significantly increase intracellular Ca2+ concentration in the presence of doxorubicin hydrochloride (DOX) and thus induce massive tumor cell apoptosis. Herein, we designed a synergistic nanoplatform that not only amplifies the intracellular Ca2+ concentration and induce cell death under mild MW irradiation but also avoids the side effect of thermal ablation and chemotherapy. RESULTS: The as-made NaCl-DOX@PLGA nanoplatform selectively elevates the temperature of tumor tissue distributed with nanoparticles under low-output MW, which further prompts the release of DOX from the PLGA nanoparticles and tumor cellular uptake of DOX. More importantly, its synergistic effect not only combines thermal ablation and chemotherapy, but also obviously increases the intracellular Ca2+ concentration. Changes of Ca2+ broke the homeostasis of tumor cells, decreased the mitochondrial inner membrane potential and finally induced the cascade of apoptosis under nonlethal temperature. As such, the NaCl-DOX@PLGA efficiently suppressed the tumor cell progression in vivo and in vitro under mild MW irradiation for the triple synergic effect. CONCLUSIONS: This work provides a biocompatible and biodegradable nanoplatform with triple functions to realize the effective tumor killing in unlethal temperature. Those findings provide reliable solution to solve the bottleneck problem bothering clinics about the balance of thermal efficiency and normal tissue protection.

Theranostic liposomes as nanodelivered chemotherapeutics enhanced the microwave ablation of hepatocellular carcinoma.

Aim: This study aimed to develop indocyanine green- and doxorubicin-loaded liposomes (DILPs) as theranostic nanoplatform for the detection of hepatocellular carcinoma (HCC) and as an efficient chemotherapeutic to enhance microwave ablation. Materials & methods: DILPs were synthesized and thoroughly characterized. Biocompatibility, tumor uptake and accumulation, and synergistic ablation-chemotherapeutic efficiency were systematically explored in them. In addition, human HCC surgical samples were used to test the affinity of DILPs for HCC. Results: The combination of microwave ablation and DILPs enhanced the ablation efficiency of HCC with apparent tumor inhibition. DILPs exhibited excellent diagnostic ability and could detect 2.5-mm HCC lesions via optoacoustic tomography imaging. DILPs had better affinity for human HCC surgical samples compared with normal liver tissue. Conclusion: Theranostic DILPs could serve as promising nanoparticles for treatment and management of HCC in the clinic.

Liposomes loading sodium chloride as effective thermo-seeds for microwave ablation of hepatocellular carcinoma.

Microwave ablation (MWA) is a promising minimally invasive therapy that has been widely used to treat hepatocellular carcinoma (HCC). However, the efficiency of MWA in treating HCC is evidently limited by the incomplete ablation of large tumors and tumors in high-risk locations. Here, we report the value of using liposomes packed with sodium chloride (NaCl-LPs) as effective thermo-seeds for MWA of HCC. The prepared liposomes exhibited excellent heat conversion ability by showing a more rapid temperature increase than free NaCl medium, blank liposomes or water under microwave irradiation. The high efficiency of this new microwave sensitization strategy was fully demonstrated in vitro in subcutaneous and orthotopic tumors. The results showed that MWA combined with NaCl-LPs clearly enhanced the ablation efficiency, leading to apparent tumor inhibition and low recurrence. What's more, we verified the susceptibility of NaCl-LPs on orthotopic tumors. Based on the unique properties of NaCl-LPs, sublethal MWA was used to mimic the transitional zone, and large-scale necrosis was observed in tumors combined with NaCl-LPs. In addition, HE staining and blood hematology analysis revealed no noticeable toxicity of NaCl-LPs in vivo, which confirmed that NaCl-LPs possessed good biocompatibility. CONCLUSION: The effective nanoparticles could play a valuable role in enhancing the thermo-sensitizing effect of MWA for achieving better therapeutic efficacy.