Photothermal agents with strong near infrared (NIR) optical absorbance and excellent biocompatibility and traceability are highly desired for precise photothermal therapy. This study reports the development of a dual-functional Fe 3+ complex (Fe-ZDS) for imaging-guided, precise photothermal therapy of tumors. The complex has stable structure and obvious zwitterionic features, resulting in excellent biocompatibility and efficient renal clearance. The iron-dopa core structure renders the complex capable of generating magnetic resonance imaging (MRI) contrast, while synergistically exhibiting optical absorption in the red and NIR regions. Interestingly, the optical absorption of the complex is pH-sensitive, with significantly higher absorption intensity in a weakly acidic environment than in a neutral environment. Thus the complex can respond to acidic tumor stimuli and confine the energy of the laser to the tumor tissue. The MRI contrast and photoacoustic signal of the complex is taken advantage of to monitor the probe injection process and optimize the injection position and dosage for maximally covering the tumor tissue and assessing the activation of the complex in tumor tissues. The evolution of temperature inside the tissue during the laser irradiation is also monitored. Using Fe-ZDS as the theranostic probe, satisfactory treatment outcomes are achieved for photothermal therapy of tumors.

Extremely small-sized iron oxide nanoparticles (ESIONs) have been accepted as a potential alternative to gadolinium-based contrast agents for enhanced T 1 -weighted MR imaging. Recently developed zwitterion-coated ESIONs showed a high T 1 contrast power and efficient renal clearing ability, but the tedious preparation steps that required high-cost, unfriendly experimental conditions and a sophisticated phase transition process would likely hinder their clinical translation. Herein, we present a one-pot gram-scale synthesis of zwitterion-capped ultrasmall iron oxide nanoparticles (ZUIONs). The nanoparticles have a core size as small as 3.7 nm and display high colloidal stability in various buffers. The r 1 relaxivity of 2.4 mM −1 s −1 and r 2 /r 1 ratio as low as 2.2 at 1.0 T guarantee their application as effective T 1 MRI contrast agents. In vivo studies showed that ZUIONs could induce a significant contrast enhancement in blood pool and be eliminated from the body mainly through the renal excretion pathway. The combined advantageous features including facile preparation, excellent biocompatibility, strong T 1 MRI contrast effect, appropriate circulation time, and renal clearable property would render ZUIONs attractive for practical applications.

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The renal-clearing feature of inorganic nanoparticles is highly desired for their transition to the clinic. Although high-quality ultrasmall inorganic nanoparticles can be routinely synthesized via the thermal decomposition method, rendering them suitable for in vivo application without enlarging their hydrodynamic size is still challenging. In this study, we report a facile and general method for phase transfer of hydrophobic inorganic nanoparticles from the organic phase to the aqueous phase using a zwitterionic silylation agent. The phase transfer process can be accomplished in one pot within minutes and was found to be suitable for a wide variety of inorganic nanoparticles. Interestingly, the resulting nanoparticles showed excellent colloidal stability, minimal effective hydrodynamic size, and low nonspecific affinities toward serum proteins. Thus, nanoparticles with the desired renal-clearing property were obtained. These features rendered the phase transfer method reported here considerably advantageous over previous polymer-based strategies and will be useful for preparing biocompatible nanomaterials for biomedical applications.

Accurate diagnosis of tumorcharacteristics, including its location andb oundary,i so fi mmense value to subsequent therapy. Activatable magnetic resonance imaging (MRI) contrasta gents that respond to tumor-specific microenvironments, such as the redox state, pH, and enzymea ctivity,e nable better mapping of tumor tissue. However,t he practical application of most reported activatable agents is hampered by problems including potential toxicity,i nefficient elimination, and slow activation. In this study,w ed eveloped az witterionic iron complex (Fe-ZDS) as ap ositive MRI contrast agent for tumor-specific imaging. Fe-ZDS could dissociate in weakly acidic solutionr apidly, accompanied by clear longitudinal relaxivity (r 1 )e nhancement, whiche nabled the complex to act as ap H-sensitive contrast agent for tumor-specific MR imaging. In vivo experiments showedt hat Fe-ZDS rapidlye nhanced the tumor-to-normal contrast ratio by > 40 %, which assisted in distinguishing the tumor boundary.F urthermore, Fe-ZDS circulated freely in the bloodstream and was excreted relativelys afely via kidneys owing to its zwitterionic nature. Therefore, Fe-ZDS is an ideal candidate for at umor-specific MRI contrast agent and holds considerable potentialfor clinical translation.Scheme1.Schematicillustration of the pH-responsiveness of Fe-ZDS and the application of the complex as as mart MRI contrastagent for in vivo tumorimaging.