Quantitative Drug Release Monitoring in Tumors of Living Subjects by Magnetic Particle Imaging Nanocomposite.

In vivo drug release monitoring provides accurate and reliable information to guide drug dosing. Image-based strategies for in vivo monitoring are advantageous because they are non-invasive and provide visualization of the spatial distribution of drug, but those imaging modalities in use (e.g., fluorescence imaging (FI) and magnetic resonance imaging (MRI)) remain inadequate because of the low tissue penetration depth (for FI) or difficulty with quantification of release rate and signal convolution with noise sources (for MRI). Magnetic particle imaging (MPI), employing superparamagnetic nanoparticles as the contrast agent and sole signal source, enables large tissue penetration and quantifiable signal intensity. These properties make it ideal for application to in vivo drug release monitoring. In this work, we design a superparamagnetic Fe3O4 nanocluster@poly(lactide-co-glycolide acid) core-shell nanocomposite loaded with a chemotherapy drug (doxorubicin) which serves as a dual drug delivery system and MPI quantification tracer. The as-prepared nanocomposite can degrade under a mild acidic microenvironment (pH = 6.5), which induces a sustained release of doxorubicin and gradual decomposition of the Fe3O4 nanocluster, causing the MPI signal changes. We showed that nanocomposite-induced MPI signal changes display a linear correlation with the release rate of doxorubicin over time (R2 = 0.99). Utilizing this phenomenon, we successfully established quantitative monitoring of the release process in cell culture. We then performed in vivo drug release monitoring in a cancer therapy setting using a murine breast cancer model by injecting the nanocomposite, monitoring the drug release, and assessing the induced tumor cell kill. This study provides an improved solution for in vivo drug release monitoring compared to other available monitoring strategies. This translational strategy using a biocompatible polymer-coated iron oxide nanocomposite will be promising in future clinical use.

Ratiometric nanothermometer in vivo based on triplet sensitized upconversion.

Temperature is an essential factor that counts for living systems where complicated vital activities are usually temperature dependent. In vivo temperature mapping based on non-contact optical approach will be beneficial for revealing the physiological phenomena behind with minimized influence to the organism. Herein, a highly thermal-sensitive upconversion system based on triplet-triplet annihilation (TTA) mechanism is pioneered to indicate body temperature variation sensitively over the physiological temperature range. The temperature-insensitive NaYF4: Nd nanophosphors with NIR emission was incorporated into the temperature-responsive TTA-upconversion system to serve as an internal calibration unit. Consequently, a ratiometric thermometer capable of accurately monitoring the temperature changes in vivo was developed with high thermal sensitivity (~7.1% K-1) and resolution (~0.1 K).

Hybrid Nanoclusters for Near-Infrared to Near-Infrared Upconverted Persistent Luminescence Bioimaging.

Persistent luminescence (PL) bioimaging provides an optimal method of eliminating autofluorescence for a higher resolution and sensitivity because of the absence of excitation light. However, ultraviolet light is still necessary in common energy charging processes, which limits its reactivation in vivo because of its low penetration depth. In the present study, we introduce a type of hybrid nanocluster (UCPL-NC) composed of upconversion nanoparticles, ß-NaYbF4:Tm@NaYF4, and persistent nanoparticles, Zn1.1Ga1.8Ge0.1O4:0.5%Cr, which can be activated by a 980 nm laser and exhibits an afterglow at 700 nm to realize near-infrared (NIR) to NIR UCPL bioimaging. The PL of the UCPL-NCs can be reactivated even when covered with a 10 mm pork. We demonstrate that these polyethylene glycol-modified phospholipid-functionalized UCPL-NCs can be reactivated in vivo and applied in the PL lymphatic imaging on small animals.

17ß-Estradiol-Loaded PEGlyated Upconversion Nanoparticles as a Bone-Targeted Drug Nanocarrier.

Hormone replacement therapy (HRT) plays an important role in the treatment and prevention of osteoporosis. Here, 17ß-estradiol (E2)-loaded PEGlyated upconversion nanoparticles (E2-UCNP@pPEG) were synthesized that retained E2 bioactivity and improved delivery efficiency over a relatively long time-period. E2-UCNP@pPEG was synthesized and characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), and Fourier transform infrared (FTIR), among other methods. The loading efficiency of E2 was determined to be 14.5 wt %, and the nanocarrier effectively facilitated sustained release. Confocal upconversion luminescence (UCL) imaging using the CW 980 nm laser as excitation resource revealed significant interactions of E2-UCNP@pPEG with preosteoblasts. E2-UCNP@pPEG treatment of preosteoblasts induced positive effects on differentiation, matrix maturation, and mineralization. Moreover, in situ and ex vivo UCL imaging studies disclosed that E2 encapsulated in the nanocomposite was passively delivered to bone. Our results collectively suggest that this nanoreservoir provides an effective drug-loading system for hormonelike drug delivery and support its considerable potential as a therapeutic agent for osteoporosis.

Lanthanide-based nanocrystals as dual-modal probes for SPECT and X-ray CT imaging.

Applications of lanthanide-based nanoparticles for bioimaging have attracted increasing attention. Herein, small size PEG-EuOF:(153)Sm nanocrystals (∼5 nm) (PEG = poly(ethylene glycol)bis(carboxymethyl)ether) combined with the radioactive and X-ray absorption properties were synthesized. The distribution of the PEG-EuOF nanocrystals in living animals was studied by ex vivo radioassay, inductively coupled plasma-atomic emission spectrum (ICP-AES) analysis and in vivo SPECT imaging, which indicated that the small size PEG-EuOF:(153)Sm had long blood retention time (blood half-life (t1/2) reach to 4.65 h) and were eliminated significantly through biliary/gastrointestinal pathway in vivo. Meanwhile, benefiting from the high attenuation ability of Eu, the small size PEG-EuOF was successfully applied for lymph node CT imaging, extending the bio-applications of these small nanocrystals. The results of cytotoxicity and in vivo toxicity also showed that the PEG-EuOF nanocrystals have relatively low toxicity, which suggest their safety for in vivo imaging. The studies provide preliminary validation for the use of PEG-EuOF nanocrystals for in vivo bioimaging applications.