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Nuclear-Targeting Gold Nanorods for Extremely Low NIR Activated Photothermal Therapy Limin Pan, Jianan Liu, and Jianlin Shi* State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai 200050, China
ACS Appl. Mater. Interfaces 2017.9:15952-15961. Downloaded from pubs.acs.org by TULANE UNIV on 01/14/19. For personal use only.
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ABSTRACT: Photorelated nanomedicine is of particular interest as an emerging paradigm toward precise cancer therapy, as demonstrated by recent developments of photothermal therapy (PTT), an emerging technique employing light-converting agents to burn cancerous cells by overdosed optical energy-converted heat. However, most of the laser irradiations needed for effective PTT significantly exceed the maximal permissible power density in human skin, which is likely to damage surrounding normal tissues. Herein, we report a strategy of intranuclear PTT of cancer enabled by nuclear-targeted delivery of gold nanorods of ∼10.5 × 40.5 nm in size via conjugation with nuclear location signal peptides (GNRs-NLS) under an extremely low nearinfrared irradiation of 0.2 W/cm2, much below the maximal permissible exposure of skin. Interestingly, we found that a mild but nuclear-focused temperature increase generated by GNRs-NLS is sufficient to cause damage to intranuclear DNA and the inhibition of DNA repair process, which, interestingly, led to the cancer cell apoptosis rather than to conventional cell necrosis by thermal ablation during PTT. Correspondingly, tumors treated with GNRs-NLS exhibited gradual but significant regressions rather than traditional harsh burning-up of tumors, in comparison with negligible antitumor effect by GNRs without nuclear targeting under the same ultralow NIR irradiation. This report demonstrates the successful intranuclear efficient photothermal therapy of cancer via cell apoptosis by photoadsorbing agents, e.g., GNRs-NLS in the present case, with largely mitigated sideeffect on normal tissues and therefore substantially improved biosafety. KEYWORDS: nuclear targeting, gold nanorods, photothermal therapy, ultralow power density, NIR irradiation, biosafety
1. INTRODUCTION Currently, cancer is the biggest threaten to humans and may lead to 13.2 million death worldwide by 2030 as forecasted by the United Nations.1 At present, the clinically used therapy strategies are mostly limited to surgery, chemotherapy, and radiotherapy. However, such approaches will inevitably damage normal tissues, destroy the immune system, and increase incidences of tumor metastasis.2,3 Photothermal therapy (PTT) has attracted great attention in tumor therapy due to its noninvasiveness and high selectivity.4,5 Photoabsorbing agents were used in PTT, converting light energy into heat and resulting in the ablation of tumors.6,7 Therefore, the PTT effects can only take place in tumor regions under the existence of both light-absorbing agents and local light irradiation, without killing normal cells.8 In the past decade, many research groups have been devoted to explore near-infrared (NIR) lightabsorbing agents because their excitation light is within the optical transparent window in tissues (700−900 nm). For example, many nanostructures, such as carbon nanomaterials (e.g., graphene and carbon nanotubes),9−12 various gold © 2017 American Chemical Society
nanomaterials (e.g., gold nanocages, nanostars, and nanorods),6,13−16 organic nanoparticles,17,18 palladium nanosheets,19 and copper-based semiconductor nanoparticles,20,21 have been developed for effective ablation of tumors. Among these nanomaterials that are currently being developed, gold nanorods (GNRs) have been widely used in PTT applications thanks to their advantages of good biocompatibility and favorable optical properties.16,22−28 In addition, GNRs can also be served as effective contrast agents for tumor diagnosis owing to their tunable and strong absorption in the NIR transparent window.24 Hence, GNRs can be anticipated to be promising therapeutic agents excited by NIR light. However, most of the currently used photothermal agents require laser irradiation with a relatively high power density, which is beyond the maximally permissible exposure (MPE) (e.g., 0.4 W/cm2 for 850 nm) in human skin set by American Received: March 1, 2017 Accepted: April 27, 2017 Published: April 27, 2017 15952
DOI: 10.1021/acsami.7b03017 ACS Appl. Mater. Interfaces 2017, 9, 15952−15961
Research Article
ACS Applied Materials & Interfaces
Figure 1. (a) Schematic illustration of the synthetic procedure of GNRs-NLS. (b) Schematic representation of nuclear targeted photothermal therapy of GNRs-NLS.
National Standards Institute.29 High-intensity laser would damage adjacent normal tissues due to nonspecific absorption. Moreover, to reach the tumor sites for necessary intratumoral therapeutic dose, enhanced energy input is required, which could cause burning, blistering, and pain on skin and normal tissues in the way of the irradiation. Insufficient intracellular agent delivery, random intracellular distribution, and low light− heat converting efficacy may be the primary barriers. Consequently, to maximize the intratumoral PTT efficacy and compensate for attenuated adverse effects by using as low as possible laser irradiation energy, the exploration of photothermal agents like GNRs for more efficient converting of NIR light energy to heat, especially with enhanced cellular uptake and localized accumulation in subcellular organelles hypersensitive to heat, is of great significance.29 With recent developments in nanotechnology, to achieve cell- and sitespecific delivery efficiently for the desired PTT treatment, the photothermal agents must be functionalized with cargoes such as peptides, antibodies, and small-molecule ligands for targeting. It has also been reported that the nuclear matrix is one of the most thermolabile structures in the cells.30 Thermal changes in the nuclear matrix would result in aggregation of proteins to the matrix, disrupting its function by inhibiting DNA supercoiling transformation and changes of specific DNA regions within the nuclear matrix. Therefore, the development of novel nuclear targeting photothermal agents with efficient photothermal conversion property, adequate biocompatibility, easy fabrication, and especially intranuclear accumulation is highly desired for subcellular targeted PTT with substantially lowered NIR exposure. Nuclear targeting of nanoparticles is particularly challenging, in which there are multiple barriers existing from the cytoplasmic membrane to the nuclear envelope.31,32 Furthermore, the exchange of cytoplasmic and nucleoplasmic has been strictly restricted by nuclear pore complexes (NPCs) that are sized ∼50 nm and serve as gatekeepers on the nuclear envelope.33 It has been demonstrated previously that ultrasmall nanoparticles (
