Science to Practice: Molecular-targeted Drug Delivery in Combination with Radiofrequency Ablation of Liver Cancer: A Magic Bullet?

By achieving higher chemotherapeutic drug concentrations in target lesions, fewer toxic effects, and improved survival end points in an animal tumor model, the authors conclude that superior tumor treatment with radiofrequency ablation is possible when combined with molecular-targeted drug delivery systems.

Summary

In an effort to improve the technical success rates and clinical outcomes of radiofrequency (RF) ablation, Yan et al validated the use of a tumor-penetrating peptide and thermosensitive doxorubicin (DOX)-loaded nanoparticles in combination with RF ablation in a hepatocellular carcinoma mouse model. By achieving higher chemotherapeutic drug concentrations in target lesions, fewer toxic effects, and improved survival end points in an animal tumor model, the authors conclude that superior tumor treatment with RF ablation is possible when combined with molecular-targeted drug delivery systems.

The Setting

RF ablation is the mainstay of therapy for small liver tumors of various types, particularly primary liver cancer. RF ablation has been incorporated in most treatment guidelines and recommendations for hepatocellular carcinoma and is currently used as the main ablation technique in early-stage hepatocellular carcinoma (1). In some scenarios, ablation is favored over surgical resection because of its lower cost and decreased morbidity and toxicity to surrounding tissue (2). Recently, RF ablation has increasingly been combined with transarterial embolotherapies or systemic chemotherapy, especially the liposomal formulation of DOX (3).

The technical success rates of RF ablation are lower in tumors of large diameter and lesions located near sensitive anatomic structures. Overall, however, incomplete ablation and local disease recurrence continue to be the most commonly reported issues limiting successful patient outcomes after ablation (1,4). The therapeutic efficacy of ablation could be improved by further improvements in the technique of ablation itself and by obtaining a better understanding of the physiologic effects of RF ablation on targeted tissue. Novel concepts that lead to improved RF ablation include adjuvant therapies that inhibit undesired molecular mechanisms set in motion by the thermal injury caused by the ablation. Other therapies seek to improve the efficacy of RF ablation through enhanced drug penetration into tumor tissue and more effective local release of chemotherapy by using nanoparticles (3,5,6).

Within this context, Yan et al (7) contribute to the refinement of RF ablation by successfully implementing two cutting-edge techniques in a well-selected animal tumor model: use of a temperature-sensitive nanoparticle that releases chemotherapy focally at specific temperatures and addition of a tumor-homing peptide to improve the penetrative ability of chemotherapeutic agents and increase drug concentrations in the target lesion while sparing healthy tissue away from the ablation zone. The observed survival benefits of this approach in an animal model suggest that these molecular techniques may be applied to RF ablation and possibly other thermal ablation techniques.

The Science

Yan et al (7) performed a scientifically sound set of experiments to first evaluate the independent and combined effects of tumor-penetrating peptide internalizing CRGDKGPDC (iRGD) and thermally sensitive liposomal (TSL) delivery of DOX (TSL-DOX) in vitro. Next, they examined the synergistic effects of these techniques (iRGD-TSL-DOX) with RF ablation of liver tumors in vivo by using a mouse model.

The molecular properties of iRGD and TSL-DOX were characterized. The authors examined the encapsulation efficiency and drug release efficacy of the nanoparticles at two temperatures over time. The temperatures, 37°C and 42°C, were chosen to represent the body temperature and the temperature at the ablation margin, respectively. This process was repeated with TSL-DOX alone and in combination with iGRD, validating the technical success of temperature-sensitive drug release. To simulate tumor adhesion rates of both treatment options (TSL-DOX and iRGD-TSL-DOX) in vivo, the authors monitored the behavior of the nanoparticles at both temperatures when applied to H22 hepatocarcinoma cells derived from an allograft mouse model. The levels of DOX concentration achieved both locally and in undesired systemic locations were tested by harvesting tumor and heart samples at different times after the two treatment options. Finally, both treatments were administered intravenously 30 minutes before RF ablation in mice. Tumors were harvested at various times and evaluated with pathologic analysis, and long-term outcomes were assessed.

The iRGD-TSL-DOX treatment resulted in a 2.7-fold higher DOX concentration in the tumor compared with TSL-DOX alone. This combined effect of tumor-penetrating peptide and temperature-sensitive nanoparticles also increased tumor cell apoptosis. In vitro models of iRGD-TSL-DOX demonstrated a single peak in DOX accumulation 1 hour after administration. Interestingly, the same model in vivo showed a second peak in drug accumulation 24 hours after administration. This additional peak in drug uptake resulted in a longer period of high drug concentrations within tumor cells, which maximized the opportunity for treatment effect. Despite these higher drug concentrations, the cardiotoxicity of DOX was limited, likely a result of the improved tumor affinity through the use of iRGD. The combination of RF ablation and iRGD-TSL-DOX inhibited tumor growth nearly completely in 25% of mice. Overall animal survival with this treatment was prolonged compared with RF ablation alone. In addition, the TSL-DOX treatment independently improved animal survival when paired with RF ablation. Contrary to the hypothesis of Yan et al (7), there was no significant difference in survival benefits between iRGD-TSL-DOX and TSL-DOX. This result suggests that the benefit of targeted drug delivery gained through iRGD alone may not be sufficient to significantly affect tumor growth in this particular animal model, and that the outcomes observed in this experiment may be primarily driven by TSL-DOX. The authors concluded that further studies are needed to evaluate these therapies in other animal models and tumor types to understand the roles of drug dosing and the tumor microenvironment as they relate to hepatocellular carcinoma and other malignancies. However, the study by Yan et al offers conclusive proof of principle for combining a systemic and locally activated chemotherapeutic agent with RF ablation.

The Practice

Clinical use: The results from Yan et al (7) are noteworthy in that they represent another valuable addition to a series of translational studies that provide a second look at all ablative modalities from the standpoint of their molecular and physiologic mechanisms of action. Ablative tumor therapies are currently undergoing a fundamental overhaul with respect to indication, molecular imaging, image guidance, and potential combinations with systemically delivered molecular-targeted agents. The research that led to the discovery of the immune-triggered so-called off-target effects of RF ablation has refuted long-standing dogmas regarding the minimally invasive aspect of this therapy (8). As for the combination of RF ablation with conventional systemically applicable and toxic agents, such as DOX, the paradigm of unacceptable systemic toxicity of such agents may also be shifting because of elegant solutions and advanced drug delivery methodologic studies such as the technique introduced by Yan et al. Specifically, the reduced cardiotoxic effects noted in this study imply that systemic toxicities may no longer be part of the equation when a combination of local-regional therapies is considered. The scientific community should continue to vigorously investigate more sophisticated tumor-targeting drug delivery systems to achieve improved tumor control without risking significant or prohibitive systemic toxicity.

Furthermore, even gradually improved technical success rates of RF ablation will help fill the gap of badly needed treatment options for liver cancer, a disease that is increasingly identified at earlier stages (because of better surveillance programs), that are amenable to ablative therapies (9).

Future opportunities and challenges: As with any in vivo experiment that employs an animal model, a substantial barrier to translating this result to clinical practice will be replicating such results in more complicated animal models and eventually patients. Given the comorbidities often observed in liver cancer, dosing regimens are not likely to be easily translated from animals to humans. Nonetheless, the results of Yan et al (7) within the framework of other technical advancements in local-regional treatments indicate that more sophisticated drug delivery systems are on the horizon and could soon emerge as the standard of care. As evidence of the success of molecular-targeted cancer therapies continues to grow, it will be critical to understand how genetic profiles and microenvironment of tumors interact with these new techniques. The future of cancer treatment is personalized medicine; looking ahead, clinicians must also begin to develop a novel practice that bridges current knowledge in tumor traits with corresponding molecular-targeting therapies on a patient-by-patient basis.