Abstract
PurposeTo determine the effect of different drug-loaded nanocarriers (micelles and liposomes) on delivery and treatment efficacy for radiofrequency ablation (RFA) combined with nanodrugs.Materials/MethodsFischer 344 rats were used (n = 196). First, single subcutaneous R3230 tumors or normal liver underwent RFA followed by immediate administration of IV fluorescent beads (20, 100, and 500 nm), with fluorescent intensity measured at 4–24 hr. Next, to study carrier type on drug efficiency, RFA was combined with micellar (20 nm) or liposomal (100 nm) preparations of doxorubicin (Dox; targeting HIF-1α) or quercetin (Qu; targeting HSP70). Animals received RFA alone, RFA with Lipo-Dox or Mic-Dox (1 mg IV, 15 min post-RFA), and RFA with Lipo-Qu or Mic-Qu given 24 hr pre- or 15 min post-RFA (0.3 mg IV). Tumor coagulation and HIF-1α orHSP70 expression were assessed 24 hr post-RFA. Third, the effect of RFA combined with IV Lipo-Dox, Mic-Dox, Lipo-Qu, or Mic-Qu (15 min post-RFA) compared to RFA alone on tumor growth and animal endpoint survival was evaluated. Finally, drug uptake was compared between RFA/Lipo-Dox and RFA/Mic-Dox at 4–72 hr.ResultsSmaller 20 nm beads had greater deposition and deeper tissue penetration in both tumor (100 nm/500 nm) and liver (100 nm) (p<0.05). Mic-Dox and Mic-Qu suppressed periablational HIF-1α or HSP70 rim thickness more than liposomal preparations (p<0.05). RFA/Mic-Dox had greater early (4 hr) intratumoral doxorubicin, but RFA/Lipo-Dox had progressively higher intratumoral doxorubicin at 24–72 hr post-RFA (p<0.04). No difference in tumor growth and survival was seen between RFA/Lipo-Qu and RFA/Mic-Qu. Yet, RFA/Lipo-Dox led to greater animal endpoint survival compared to RFA/Mic-Dox (p<0.03).ConclusionWith RF ablation, smaller particle micelles have superior penetration and more effective local molecular modulation. However, larger long-circulating liposomal carriers can result in greater intratumoral drug accumulation over time and reduced tumor growth. Accordingly, different carriers provide specific advantages, which should be considered when formulating optimal combination therapies.
Highlights
Radiofrequency ablation (RFA) is a mainstay treatment for primary and secondary small focal tumors in the liver, lung, kidney, and other organs, with long-term studies demonstrating good outcomes in well-selected patient populations [1,2]
No difference in tumor growth and survival was seen between RFA/liposomal quercetin (Lipo-Qu) and RFA/micellar quercetin (Mic-Qu)
Larger long-circulating liposomal carriers can result in greater intratumoral drug accumulation over time and reduced tumor growth
Summary
Radiofrequency ablation (RFA) is a mainstay treatment for primary and secondary small focal tumors in the liver, lung, kidney, and other organs, with long-term studies demonstrating good outcomes in well-selected patient populations [1,2]. Strategies to target residual viable tumor cells and achieve a more complete treatment are being actively pursued One such strategy has been to combine RF ablation with chemotherapy delivered in liposomal nanocarriers to target partially-injured viable cells in the ablation zone and surrounding periablational rim [5,6,7]. In the case of liposomal quercitin, marked reduction in the thickness of the rim of HSP was noted, persistence of more peripheral expression of HSP was seen. This provides ample rationale for further study to uncover the optimal nanocarriers to be used in the setting of ablation
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