DNA Self-Assembly of Targeted Near-Infrared-Responsive Gold Nanoparticles for Cancer Thermo-Chemotherapy

The development of external stimulus-responsive nanoparticle (NP) systems for cancer therapy has received considerable attention in recent years, as these systems can differentially increase drug accumulation at target cancer cells/tissues, drastically decrease systemic toxicity, and potentially avoid underor over-dosing. External stimuli that have been exploited for such applications include light, magnetic field, ultrasound, and electricity. Among them, nearinfrared (NIR) light (650–900 nm) has recently become an attractive stimulus because of its minimal absorbance by skin and tissue, thus allowing for noninvasive and deep tissue penetration. In particular, NIR light can be effectively converted into heat by using photothermal NPs, such as gold nanorods (NRs), gold nanoshells, hollow gold nanospheres, and carbon nanotubes. As such, NIR-responsive NP platforms offer several important benefits for cancer therapy. For example, NIR-induced local heating can be used for cancer thermotherapy. In addition, NIR-responsive NP delivery systems enable on-demand release of drugs for cancer chemotherapy, presumably by heat-induced disruption of the delivery vehicles. Furthermore, the combination of NIR-based thermotherapy and triggered chemotherapy (thermo-chemotherapy) could provide higher therapeutic efficacy than respective monotherapies. In addition to these advantages, investigators are exploring the possibility of integrating active targeting ligands in NIR-responsive NP platforms for targeted cancer thermochemotherapy. This triple combination of thermotherapy, triggered drug release, and targeted delivery, would achieve optimal therapeutic efficacy in cancer treatment, relative to pairwise combinations. For example, Lee et al. have designed folate-conjugated, doxorubicin (Dox) loaded poly(lactic-co-glycolic acid) (PLGA)–gold half-shell NPs, and this combination led to effective tumor elimination in target tissues in a NIR-responsive manner. A current strategy in formulating this targeted NIR-responsive NP requires multiple steps, including 1) the synthesis of drug-loaded NPs, 2) deposition of gold compositions on NPs, and 3) postconjugation with targeting ligands followed by purification. However, these complex processes could increase the difficulty of adjusting bio-physicochemical properties of NPs in a reproducible manner, and could contribute to unintended drug release from NPs, thereby resulting in unfavorable batch-to-batch variability in the characteristics of drug loading. Alternatively, using pre-functionalized components to self-assemble into targeted NPs would eliminate the need for post-modification of NPs and is amenable to being scaledup with little batch-to-batch variability. This self-assembly strategy has led to the clinical translation of first-in-man targeted cyclodextrin-based NPs for small interfering RNA (siRNA) delivery, and targeted PLGA-based NPs for docetaxel delivery. Nevertheless, use of such a self-assembly strategy in the design of targeted NIR-responsive NPs has not been reported to date. Inspired by nature and the ability of complimentary strands of DNA to hybridize, we designed a DNA-based platform that can self-assemble into targeted NIR-responsive NPs for cancer therapy. As illustrated in Figure 1, this platform comprises three distinct functional components: complementary DNA strands, the gold NR (50 nm 10 nm), and a polyethylene glycol (PEG) layer. The DNA strands, which consist of sequential CG base pairs, provide loading sites for Dox, a model chemotherapeutic drug. By changing the number of CG base pairs, drug loading can be precisely tuned. In addition to serving as drug-loading scaffold, one strand of the DNA (termed capture strand) is thiolated for gold NR capture, and the complementary strand (termed targeting strand) is pre-conjugated with ligands for cellspecific targeting. Gold NRs serve as the model NIR light-to[*] Dr. Z. Xiao, Dr. C. Ji, Dr. J. Shi, J. Frieder, Dr. J. Wu, Prof. O. C. Farokhzad Laboratory of Nanomedicine and Biomaterials Department of Anesthesiology, Brigham and Women’s Hospital Harvard Medical School, Boston, MA, 02115 (USA) E-mail: ofarokhzad@zeus.bwh. harvard.edu