Silica-coated gold nanorods with hydrophobic modification show both enhanced two-photon fluorescence and ultrasound drug release.

Hydrophobically-modified silica-coated gold nanorods are presented here as multifunctional theranostic agents. A single modification both increases two-photon fluorescence and promotes cavitation-based acoustic signal for imaging. A two-fold greater release of small molecule drugs was observed under ultrasound-mediated conditions as compared to passive release without ultrasound.

Enzyme Prodrug Therapy with Photo-Cross-Linkable Anti-EGFR Affibodies Conjugated to Upconverting Nanoparticles.

In this work, we demonstrate that a photo-cross-linkable conjugate of upconverting nanoparticles and cytosine deaminase can catalyze prodrug conversion specifically at tumor sites in vivo. Non-covalent association of proteins and peptides with cellular surfaces leads to receptor-mediated endocytosis and catabolic degradation. Recently, we showed that covalent attachment of proteins such as affibodies to cell receptors yields extended expression on cell surfaces with preservation of protein function. To adapt this technology for in vivo applications, conjugates were prepared from upconverting nanoparticles and fusion proteins of affibody and cytosine deaminase enzyme (UC-ACD). The affibody allows covalent photo-cross-linking to epidermal growth factor receptors (EGFRs) overexpressed on Caco-2 human colorectal cancer cells under near-infrared (NIR) light. Once bound, the cytosine deaminase portion of the fusion protein converts the prodrug 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil (5-FU). NIR covalent photoconjugation of UC-ACD to Caco-2 cells showed 4-fold higher retention than observed with cells that were not irradiated in vitro. Next, athymic mice expressing Caco-2 tumors showed 5-fold greater UC-ACD accumulation in the tumors than either conjugates without the CD enzyme or UC-ACDs in the absence of NIR excitation. With oral administration of 5-FC prodrug, tumors with photoconjugated UC-ACD yielded 2-fold slower growth than control groups, and median mouse survival increased from 28 days to 35 days. These experiments demonstrate that enzyme-decorated nanoparticles can remain viable after a single covalent photoconjugation in vivo, which can in turn localize prodrug conversion to tumor sites for multiple weeks.

Hydrophobically Modified Silica-Coated Gold Nanorods for Generating Nonlinear Photoacoustic Signals.

In this work, we report that gold nanorods coated with hydrophobically-modified mesoporous silica shells not only enhance photoacoustic (PA) signal over unmodified mesoporous silica coated gold nanorods, but that the relationship between PA amplitude and input laser fluence is strongly nonlinear. Mesoporous silica shells of ~14 nm thickness and with ~3 nm pores were grown on gold nanorods showing near infrared absorption. The silica was rendered hydrophobic with addition of dodecyltrichlorosilane, then re-suspended in aqueous media with a lipid monolayer. Analysis of the PA signal revealed not only an enhancement of PA signal compared to mesoporous silica coated gold nanorods at lower laser fluences, but also a nonlinear relationship between PA signal and laser fluence. We attribute each effect to the entrapment of solvent vapor in the mesopores: the vapor has both a larger expansion coefficient and thermal resistance than silica that enhances conversion to acoustic energy, and the hydrophobic porous surface is able to promote phase transition at the surface, leading to a nonlinear PA response even at fluences as low as 5 mJ cm-2. At 21 mJ cm-2, the highest laser fluence tested, the PA enhancement was >12-fold over mesoporous silica coated gold nanorods.

Phospholipid-Coated Hydrophobic Mesoporous Silica Nanoparticles Enhance Thrombectomy by High-Intensity Focused Ultrasound with Low Production of Embolism-Inducing Clot Debris.

Here we report the efficacy of a nanoparticle-assisted high-intensity focused ultrasound (HIFU) treatment that selectively destroys blood clots while minimizing generation of microparticles, or microemboli, that can cause further complications postsurgery. Treatment of malignant blood clots (thrombi) and the resulting emboli are critical problems for numerous patients, and treatments addressing these conditions would benefit from advancements in noninvasive procedures such as HIFU. While recanalization of occlusive blood clots is currently addressed with surgical intervention that seeks to minimize formation of large emboli, there is a danger of microemboli (micrometer-size particles) that have been theorized to be responsible for the poor correlation between apparent surgical success and patient outcome. Here, the addition of phospholipid-coated hydrophobically modified silica nanoparticles (P@hMSNs) improved the efficacy of HIFU treatment by serving as cavitation nuclei for mechanical disruption of thrombi. This treatment was evaluated for the ability to clear the HIFU focal area of a thick and dense thrombus within 10 min. Moreover, it was found that the use of P@hMSN+HIFU treatment generated a significantly smaller microembolic load as compared to comparison techniques, including a HIFU + microbubble contrast agent, HIFU alone, and direct mechanical disruption. This reduction in the microembolic load can occur either with primary removal of the clot by P@hMSN+HIFU or by insonation of the clot fragments after mechanical thrombectomy. Lastly, this method was evaluated in a flow model, where nonocclusive model thrombi and model emboli were mechanically ablated within the focal area within 15 s. Together, these results represent a combination therapy capable of resolving thrombi and microembolisms resulting from thrombectomy through localized destruction of clotted material.