Nanomedicines could revolutionize thermal therapy in oncology

Technologies that enable thermal therapy treatments are now clinically viable and most ongoing hyperthermia clinical trials in oncology incorporate chemotherapy. Given the extensive list of chemotherapies that are enhanced by hyperthermia and the ability of thermosensitive nanomedicines to deliver increased amounts of drug to tumors, while not relying on the EPR effect, there is real opportunity for the clinical translation of thermosensitive nanomedicines. To realize this potential, improved thermosensitive nanomedicines encapsulating a wider range of drugs must be developed and advanced into clinical trials.

Thermal therapies alter body temperature in order to produce a therapeutic effect and include ablation (>50C) [1], hyperthermia (∼40–45C) [2], and cryoablation (<−40C) treatments [3]. The road to clinical acceptance of thermal therapy has been long and tortuous. Despite a period of optimism in the 1970s and 80s, thermal therapy was hampered by inadequate technologies for energy deposition and invasive thermometry and fell out of favor in the 1990s [4]. The field of thermal therapy has recently undergone significant improvements in both the ability to accurately and precisely elevate temperatures in a variety of tissues throughout the body [2,5] as well as the ability to accurately measure temperature spatially and temporally [6,7]. These advances have led to the clinical acceptance of tumor ablation therapy for treatment of various cancers including lung, liver, renal, and bone [8] and have made hyperthermia a viable treatment option for a variety of solid tumors [9,10]. However clinical adoption of hyperthermia treatment has been limited, particularly in North America. This is largely due to the failure of early multi-institutional randomized trials that used inadequate heating technology [11,12] and thus created the impression that the method is ineffective against cancer.

Clinically, hyperthermia can be delivered using several different approaches including: microwave [13], radio-frequency [14], infrared [15], or focused ultrasound [16] energy sources as well as magnetic fluid hyperthermia [17] or intracavitary perfusion [18]. Each of these methods has advantages and disadvantages and one has to be to be careful to select an appropriate method for a given tumor. Furthermore, while these technologies can also be employed in the preclinical setting, ease of delivery, access to equipment, cost, and the desire to perform high throughput studies often result in use of warm water or air [19–21] as the preferred approaches to heat animal tumors. However, the use of these low cost and accessible heating methods can potentially result in inadequate heating or produce different physiological thermoregulatory effects. Previous preclinical studies have shown thatthe method of heating can have a profound effect on therapeutic efficacy [22,23]. Thermosensitive nanoscale drug carriers have long been studied in combination with hyperthermia [24], with a particular focus on applications in oncology [25]. Compared to traditional (i.e. non-thermosensitive) nanomedicines, hyperthermia-triggered release formulations have the potential to increase the concentration of free drug in tumors relative to normal tissue [26] and improve patient outcomes.

Hyperthermia can have direct cytotoxic effects depending on the time and temperature of application. Yet, from our perspective, the most promising application of hyperthermia lies in its ability to act as a potent sensitizer of both radiotherapy and chemotherapy. In particular given that the temperature and duration of hyperthermia can be optimized such that it is almost completely absent of treatment-related normal tissue toxicities [41]. Thus far, the most promising clinical use of hyperthermia has been in combination with radiotherapy to treat cervical cancer [42], breast cancer [43], head and neck cancer [44], melanoma [45], and soft-tissue sarcoma [46]. However, a significant body of research has demonstrated enhanced in vitro efficacy for several distinct chemotherapeutic agents when applied in conjunction with hyperthermia [47]. Preclinical studies have demonstrated that when hyperthermia treatment is applied in vivo, a host of biological functions that affect drug transport and cytotoxicity are altered, thus modulating chemotherapeutic efficacy [48–50]. The factors that are altered by hyperthermia include: blood flow [51], blood perfusion [21], vascular permeability [52], cellular uptake [28], interstitial fluid pressure [53], hypoxia [53], immune response [54], and DNA damage repair [9]. Given that hyperthermia treatments are complex processes involving significant infrastructure costs, treatment times, and clinical expertise [55,56], it is incumbent that the selected companion chemotherapy represents the best possible treatment for patients.

In preclinical studies, thermosensitive nanomedicine formulations of chemotherapeutic agents that release drug in response to elevated temperatures have been demonstrated to produce elevated drug concentrations within tumors when administered in combination with hyperthermia and often result in an elevated maximum tolerated dose in comparison to administration of free drug [26,57–59]. Importantly, such a treatment regimen preserves the associated synergies between chemotherapy and hyperthermia. To date, the majority of thermosensitive nanomedicines are liposomes with a bilayer transition temperature in the range of 39–42 ?C which is associated with an increase in the permeability of the lipid bilayer [60]. This field is relatively mature with Yatvin et al. [24] having described the first such thermosensitive liposome in 1978. Since that time many research groups have demonstrated the preclinical superiority of a variety of thermosensitive nanomedicines compared to free drug when both are administered in combination with hyperthermia [61–63]. Consistent with this published research, our own preclinical studies in a multitude of murine models demonstrate a clear survival benefit of hyperthermia combined with thermosensitive liposomes compared to hyperthermia administered in combination with free drug [64,65].

Despite extensive preclinical research, clinical success has proven elusive with no thermosensitive nanomedicines receiving clinical approval and only ThermoDox® (Celsion Corp) entering clinical evaluation [66]. Originally developed as low temperature sensitive liposomes (LTSL) in the laboratories of David Needham and Mark Dewhirst [62], ThermoDox is currently undergoing two advanced stage clinical trials: one for the treatment of hepatocellular carcinoma in combination with ablation [67] and one for treatment of recurrent chest wall breast cancer in combination with hyperthermia [68]. Remarkably, of the 198 current clinical trials combining chemotherapy and hyperthermia, only two make use of heat-triggered release formulations (Fig. 3) [69]. Given the improvement in preclinical therapeutic efficacy that thermosensitive nanomedicines afford, in comparison to conventional therapy, this disparity in clinical practice is disappointing. It is likely that the slow clinical progress of ThermoDox has adversely impacted development in the thermosensitive nanomedicine field. The results of Celsion’s two most advanced ongoing clinical trials are eagerly anticipated by both the drug delivery and thermal therapy communities. Additionally, treatments involving hyperthermia, particularly those that incorporate thermosensitive chemotherapy, are complex procedures that require the involvement of a diverse team of healthcare and scientific professionals. While this is potentially a barrier to clinical implementation, the age of precision medicine is upon us and as such it is recognized that diverse health teams must work together in the best interests of the patient [70].

Increasing attention should be paid to the clinical development of thermosensitive nanomedicines, particularly in light of the increasing maturity of the clinical hyperthermia field. While the scale up and manufacturing of nanomedicines is not as straightforward as small molecule agents, in the case of thermosensitive liposomes, the pharmaceutical industry can rely on its expertise in bringing numerous non-thermosensitive liposome formulations to market [71]. Furthermore, while this article focuses on the employment of thermosensitive drug formulations in combination with hyperthermia, the most advanced clinical application of thermosensitive nanomedicine-based drug delivery is in combination with ablation therapy [67]. At the margins of the ablation zone, sublethal temperatures are reached and administration of thermosensitive nanomedicines results in temperature-mediated drug release which provides site-specific tumor control in these regions [72].

Currently, there is much skepticism in the field of nanomedicine-based anti-cancer drug delivery stemming from difficulties in translating preclinical success into clinical impact [73,74]. One of the reasons posited for this failure in clinical translation is the heterogeneity in the enhanced permeability and retention (EPR) effect [75]. For decades the EPR effect has been relied upon as a universal approach to target nanomedicines to solid tumors (Fig. 4). While this phenomenon is widespread and easily exploited in animal models of cancer that are currently used for drug development, there is evidence that patient-to-patient variability exists in humans [76]. The limited translation of findings from preclinical to clinical studies is often attributed to differences in the nature and properties of tumor stroma between animal models and humans [77–79]. Thermosensitive nanomedicines are not dependent on the EPR effect when hyperthermia is applied prior to or quickly following drug administration, thereby triggering drug release within the vascular space [80,81]. This treatment paradigm both allows for maximum triggered drug release [80] and mirrors the optimal administration sequence for classical chemotherapies and hyperthermia wherein simultaneous administration has been demonstrated to be advantageous [82,83]. An additional enticement for nanomedicine scientists to collaborate with their hyperthermia counterparts is the potential for non-thermosensitive nanomedicine efficacy to be enhanced by hyperthermia [52]. Traditional nanomedicines release their drug cargo more slowly than thermosensitive nanomedicines; thus, hyperthermia benefits related to cellular accumulation and sensitization are likely mitigated. However, hyperthermia-induced increases in blood flow and vascular permeability have been shown to enhance the EPR effect for traditional nanomedicines [84].

The title of this article suggests the ability of nanomedicinebased drug delivery to improve the clinical prospects of thermal therapy, but in truth both fields have much to gain from active collaboration, particularly with regards to clinical trials. At a time when nanomedicines for cancer treatment are facing increased skepticism with regards to their potential for clinical translation, engineering advances in thermal therapy are creating new opportunities for thermosensitive nanomedicines relying instead on intravascular drug release. The field of nanomedicines in oncology would do well to take advantage of this opportunity by improving both the quality and quantity of thermosensitive nanomedicine-based chemotherapies and working closely with the thermal therapy community. However, in order to fully realize a future of increased clinical translation and improved patient outcomes, those in both the hyperthermia and thermosensitive drug delivery fields need to be strong advocates for their disciplines when engaging others in the oncology community in order to build the strong collaborations necessary for future success.

Acknowledgements

CA acknowledges a Discovery grant from NSERC, Operating grant from CIHR, and a Chair in Pharmaceutics and Drug Delivery from GSK. MD acknowledges scholarships from the Dean’s Fund, Center for Pharmaceutical Oncology, and OGS. Images from Servier Medical Art by Servier have been used under a Creative Commons Attribution 3.0 Unported License.

Author affiliations: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada; Physical Sciences, Odette Cancer Research Program, Sunnybrook Research Institute, Toronto, ON, M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada; Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, M5S 3E5, Canada.

This article was originally published in Nano Today 16 (2017) 9-13.

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