Photo-thermal tumor ablation in mice using near infrared-absorbing nanoparticles
Introduction
The destruction of solid tumors using hyperthermia has been under investigation for some time. Previously investigated thermal therapies have employed a variety of heat sources including laser light, [1], [2], [3], [4] focused ultrasound, [5] and microwaves [6], [7], [8]. The benefits of thermal therapeutics over conventional resection are numerous; most approaches are minimally or non-invasive, relatively simple to perform, and have the potential of treating embedded tumors in vital regions where surgical resection is not feasible. However, in order to reach underlying tumors or to treat large tumors, the activating energy source must sufficiently penetrate healthy tissues. Unfortunately, simple heating techniques have trouble discriminating between tumors and surrounding healthy tissues, and often heat intervening tissue between the source and the target site. Several groups have investigated treatment of tumors via hyperthermia using deep penetrating near infrared (NIR) lasers with or without contrast enhancing agents (indocyanine green); however, success with current systems has been modest [1], [9], [10].
This study introduces a new laser-induced thermal therapy employing systemically delivered, NIR absorbing nanoparticles called nanoshells. Nanoshells are a new class of optically tunable nanoparticles composed of a dielectric core (silica) coated with an ultrathin metallic layer (gold) [11]. By adjusting the relative core and shell thickness, nanoshells can be manufactured to absorb or scatter light at a desired wavelength across visible and NIR wavelengths. This optical tunability permits the fabrication of nanoshells with a peak optical absorption in the NIR, a region of light where optical penetration through tissue is optimal [12]. Furthermore, the metal shell of the nanoshell converts absorbed light to heat with an efficacy and stability that far exceeds that of conventional dyes investigated earlier. Nanoshells possess absorption cross sections that are six orders of magnitude larger than indocyanine green, making this material a much stronger NIR absorber, and therefore a more effective photothermal coupling agent [13]. In addition, a nanoshell's absorption properties are dependent upon the material's rigid metallic structure rather than the more labile molecular orbital electronic transitions of conventional dyes. This makes nanoshells less susceptible to photobleaching, a problem commonly associated with dyes. The efficacy of nanoshells as a NIR absorber has already been demonstrated in a series of in vivo magnetic resonance thermal imaging (MRTI) studies examining temperature profiles of nanoshell-loaded tumors irradiated with NIR light. These studies found nanoshells absorb NIR light and generate increased temperatures sufficient to produce irreversible photo-thermal damage to subcutaneous tumors [14].
As a biomaterial, nanoshells are composed of elements generally understood to be biocompatible. The metal surface of the nanoshells employed here consists of gold, an inert metal well known for its biocompatibility. To further improve biocompatibility, ‘stealthing’ polymers like poly(ethylene glycol) (PEG) can be grafted to nanoshell surfaces using simple molecular self assembly techniques [15]. It has been demonstrated that stealthing liposomes as well as other biomolecules and materials with PEG suppresses immunogenic responses, improving blood circulation times and overall material/implant performance [16], [17].
Substantial prior research has investigated the delivery of macromolecules and small particles through the tumor vasculature. It has been demonstrated that macromolecules and small particles in the 60–400 nm size range will extravasate and accumulate in tumors [18], [19], [20], [21], [22] via a passive mechanism referred to as the ‘enhanced permeability and retention’ (EPR) effect [23], [24]. This behavior has been attributed to the leaky nature of tumor vessels, which contain wide interendothelial junctions, an incomplete or absent basement membrane, a dysfunctional lymphatic system, and large numbers of transendothelial channels [19], [25]. NIR absorbing nanoshells can be manufactured within size ranges that should demonstrate the same preferential, size-dependent accumulation in tumors via the EPR effect.
This report describes a new technique that exploits the optical, chemical and physical properties of nanoshells in conjunction with the deep penetrating properties of NIR light for a targeted, minimally invasive photothermal therapy. The principle goal of this project was to determine the efficacy of NAPT using nanoshells fabricated of an appropriate size for extravasation into tumors with optical absorption in the NIR. Subcutaneous tumors were grown in mice, solutions of PEG-coated (or ‘PEGylated’) nanoshells were injected intravenously, and accumulation within the tumor was monitored. Nanoshell-treated tumors and nanoshell-free shams were then exposed to NIR light. Resultant heating and therapeutic efficacy was assessed via surface temperature measurements, monitoring of tumor growth/regression, and animal survival times.
Section snippets
Synthesis of thiolated polyethylene glycol (PEG-SH)
PEG with a terminal thiol group (PEG-SH) was synthesized by reacting PEG-amine (MW 5000, chromatographically pure, Nektar) with 2-iminothiolane (Sigma) for 1 hour. The product was then dialyzed (MWCO 3500 dialysis cassette, Pierce) against deionized (DI) H2O for 6–8 hours to remove excess reagent. The PEG-SH yield was determined colorimetrically at 412 nm after reaction with Ellman's Reagent (5,5′-Dithio-bis(2-Nitrobenzoic Acid), Sigma). The product was stored in aliquots at −20 °C.
Gold-silica nanoshell fabrication
Nanoshells
Results and discussion
Surface temperature measurements were obtained during each NIR laser treatment for the 15 mice in the nanoshell and sham treatment groups as described. The surface temperature is a surrogate for temperatures achieved within the tumors of the NAPT treatment group as well as a measurement of thermal absorption by skin and tissue in both laser treated groups. By 30 s, the mean temperature of the laser/nanoshell treated tumors (∼50 °C) was significantly higher than NIR treated but nanoshell-free
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