Nanomedicine for Targeted Photothermal Cancer Therapy: Where are We Now?

Keywords::

• clinical translation
• nanomedicine
• photothermal therapy
• tumor targeting

Thermal treatment (or hyperthermia) of tumors has a long history, dating back to the 19th century, when a partial tumor regression was observed in patients with a fever. Through great efforts in developing technology for controlled and localized heating, as well as better understanding of the mechanisms behind temperature-induced cell killing, modern thermal treatment has proven to be effective alone or when combined with other cancer treatments, such as radiation therapy and chemotherapy [1].

Although still in the early stages of development, ideal photothermal therapy (PTT) refers to treating cancer by targeted delivery of biocompatible photothermal nanoparticles and heat to the site of interest without damaging the surrounding healthy tissue. Well-designed nanoparticles will generate heat after the absorption of nontoxic light, which is usually in the near-infrared (NIR) range (650–900 nm), for the killing of cancer cells. Considering the limited penetration depth (a few centimeters) of NIR light, as well as the varied locations of tumors in humans, the delivery of localized light may be either invasive or noninvasive. The efficiency of in vivo PTT depends greatly on the accumulation of light-responsive nanoparticles, the light-to-heat conversion efficiency and the light dose (i.e., light power density and light exciting time).

Many nanomaterials of interest are currently being investigated for PTT, such as: noble metal nanostructures, such as gold (Au) nanoshells, Au nanorods, Au nanocages and palladium nanosheets [2,3]; carbon-based nanostructures, such as single- or multi-walled carbon nanotubes [4], graphenes and their derivatives [5,6]; copper-based nanocrystals, such as copper sulfide and copper selenide [7,8]; and porphyrin-based nanoassemblies, such as porphysomes and nanoporphyrin [9,10]. Although encouraging photothermal ablation of tumors in small animals has been reported using these nanoparticles over the last decade [11], clinical translation is extremely slow, as very few of these approaches are now under clinical trials.

Translational research of Au nanoshells

Initially invented by Naomi Halas and Jennifer West from Rice University in the mid-1990s, PEGylated silica-cored Au nanoshells are the first photothermal nanoparticles to have advanced into clinical trials, appearing as AuroShell^® (Nanospectra Biosciences, TX, USA) particles in 2008 [12]. Preclinical studies confirmed the accumulation of nanoshells in tumors based on the enhanced permeability and retention effect after intravenous injection in mice [13]. Thermal ablation could then be achieved by the illumination of the tumor using NIR (808 nm) laser light delivered via fiber optics. Because nanoshells do not accumulate in healthy tissue, this AuroLase^® therapy enabled the precise thermal ablation of the tumor along its irregular boundaries while preserving the surrounding healthy tissue. A biomedical company named Nanospectra Biosciences was founded to promote this technology.

Before clinical trials, systematic toxicity studies in mice, rats and dogs were also carried out based on the International Organization for Standardization (ISO)-10993 guidance standards for the biological evaluation of a medical device in order to fully investigate the biodistribution, clearance and acute toxicity of Au nanoshells [14]. Although long-term retention of the nanoshells in the reticuloendothelial system (the liver and spleen) was observed, no obvious toxicity was indicated in any of these studies. Similar issues are also seen in other nanoparticles of similar sizes, making this an unsurprising result.

An efficacy study of AuroLase therapy in patients with primary and/or metastatic lung tumors is ongoing (NCT01679470) in the USA. Patients are given a systemic intravenous infusion of Au nanoshells and a subsequent escalating dose of laser radiation delivered by optical fibers via bronchoscopy. A second clinical trial is aiming to focus on treating patients with refractory and/or recurrent tumors of the head and neck (NCT00848042). Although the addition of targeting ligands to the surface of Au nanoshells could potentially improve their accumulation in tumors, as evidenced by the successful vascular-targeted PTT of glioma in mice [15], to date, Au nanoshells are expected to accumulate in patients purely based on the enhanced permeability and retention effect in these two clinical trials.

New photothermal nanoparticles

Despite the long and costly process (10–15 years and millions of US dollars) of the first case of translating Au nanoshells to the clinic, preclinical studies with many newly discovered photothermal agents in laboratories around the world have shown encouraging results. For example, freestanding hexagonal palladium nanosheets with a thickness of less than 10 atomic layers were synthesized using carbon monoxide as a surface-confining agent. As-prepared nanosheets exhibited a well-defined but tunable surface plasmon resonance peak in the NIR region and enhanced photothermal stability when compared with conventional Au or silver nanostructures [3]. Copper selenide (Cu_2-xSe) nanocrystals are another new type of photothermal agent with strong NIR optical absorption and a high molar extinction coefficient (7.7 × 10⁷ cm^-1M^-1 at 980 nm) [8]. Through doping with copper-64 (⁶⁴Cu; a radioisotope with a 12.7-h half-life), researchers also succeeded in integrating intrinsic PET imaging with PTT by developing [⁶⁴Cu]CuS nanoparticles [7]. Although preliminary toxicity studies showed negative results in all of these newly developed nanoparticles, more systematic and long-term in vivo studies in different species are needed before clinical translation.

In addition to the aforementioned inorganic-based photothermal agents, biodegradable porphyrin-based nanoassemblies are attractive organic nanomedicine agents that hold greater potential for clinical translation due to their simplicity and high biocompatibility [9,10]. In one study, porphysomes with unique photothermal and photoacoustic properties were synthesized from self-assembled phospholipid–porphyrin bilayers [9]. As-synthesized porphysomes were enzymatically biodegradable and induced only minimal acute toxicity in mice with an extremely high intravenous dose (1000 mg/kg). The potential of porphysomes as nanocarriers for loading ⁶⁴Cu (or Mn³⁺ ions) in ordr to form an intrinsic PET (or MRI) agent has also been demonstrated recently [16,17], highlighting their great potential as a novel biodegradable theranostic nanomedicine.

Conclusion

The last decade has demonstrated that nanomedicine-based PTT is a highly promising cancer management technique. Although the photothermal nanoparticles reported so far have been focused on proof-of-concept PTT demonstrations in small animals, we believe that more clinical trials of photothermal nanoparticles will be approved by the US FDA, and the currently ongoing clinical trials of Au nanoshells will bring us one step closer to curing cancer by targeted PTT.

Future perspective

Preclinical research of PTT will continue to grow quite quickly in the next decade. Although adding targeting ligands to the surface of photothermal nanoparticles could mean additional synthetic steps, costs and greater regulatory hurdles during good manufacturing practice [18], the engineering of tumor actively targeted photothermal nanoparticles holds a greater chance for higher accumulation efficacy of nanoparticles in the tumor site and will become one of the important directions for research in the next few years. Image-guided PTT and the combination of thermal therapy with conventional chemotherapy will be other promising research areas, considering that most photothermal nanoparticles are also photoacoustic imaging agents [19] and the already-demonstrated synergistic effects of thermochemotherapy (or thermoradiotherapy) [20].

Great challenges still exist for pushing photothermal nanoparticles from the bench to bedside. Caution needs to be taken when selecting the best nanoplatform. Nanoparticles that contain heavy metal elements or cannot be degraded in vivo may find it difficult to be approved by the FDA due to their long-term toxicity concerns. Thus, liposome-like and biodegradable porphysomes with a strong NIR absorption capability might become the next promising nanomedicines for entering clinical trials. In addition, most nanoparticles are known to lose their uniformity and reproducibility when production is scaled up. Therefore, great efforts are needed in order to ensure the high quality control (e.g., good laboratory practice and good manufacturing practice) of nanoparticles that are to be translated. Finally, closer partnership among academic researchers, clinicians, pharmaceutical industries, the National Cancer Institute and the FDA is necessary in order to promote the translational research of promising photothermal nanoparticles.

Acknowledgements

The authors would like to thank EB Ehlerding for helpful proofreading.

Financial & competing interests disclosure

This work is supported, in part, by the University of Wisconsin–Madison, the NIH (NIBIB/NCI 1R01CA169365, P30CA014520), the Department of Defense (W81XWH-11-1-0644) and the American Cancer Society (125246-RSG-13-099-01-CCE). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work is supported, in part, by the University of Wisconsin–Madison, the NIH (NIBIB/NCI 1R01CA169365, P30CA014520), the Department of Defense (W81XWH-11-1-0644) and the American Cancer Society (125246-RSG-13-099-01-CCE). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.