To achieve the accurate diagnosis of tumor with the magnetic resonance imaging (MRI), nanomaterials-based contrast agents are developed rapidly. Here, a tumor targeting nanoprobe of c(RGDyK) modified ultrasmall sized iron oxide is reported with high saturation magnetization and high T 1 -weighted imaging capability, attributed to a large number of paramagnetic centers on the surface of nanoprobes and rapid water proton exchange rate (inner sphere model), as well as strong superparamagnetism (outer sphere model). These nanoprobes could actively target and gradually accumulate at the tumor site with a time-dependent T 1 –T 2 contrast enhancement imaging effect. In in vivo MRI experiments, the nanoprobes exhibit the best T 1 contrast enhancement at 30 min after intravenous administration, followed by gradually vanishing and generating T 2 contrast enhancement with increasing time at tumor site. This is likely due to time-dependent nanoprobes aggregation in tumor, in good agreement with in vitro experiment where aggregated nanoprobes display larger r 2 / r 1 value (19.1) than that of the dispersed nanoprobes (2.8). This dynamic property is completely different from other T 1 -T 2 dual-modal nanoprobes which commonly exhibit the T 1 - and T 2 -weighted enhancement effect at the same time. To sum up, these c(RGDyK) modified ultrasmall Fe 3 O 4 nanoprobes have significant potential to improve the diagnostic accuracy and sensitivity in MRI.
Surgical resection remains the preferred approach for some patients with glioblastoma (GBM), and eradication of the residual tumour niche after surgical resection is very helpful for prolonging patient survival. However, complete surgical resection of invasive GBM is difficult because of its ambiguous boundary. Herein, a novel targeting material, c(RGDyk)-poloxamer-188, was synthesized by modifying carboxyl-terminated poloxamer-188 with a glioma-targeting cyclopeptide, c(RGDyk). Quantum dots (QDs) as fluorescent probe were encapsulated into the self-assembled c(RGDyk)-poloxamer-188 polymer nanoparticles (NPs) to construct glioma-targeted QDs-c(RGDyk)NP for imaging-guided surgical resection of GBM. QDs-c(RGDyk)NP exhibited a moderate hydrodynamic diameter of 212.4 nm, a negative zeta potential of –10.1 mV and good stability. QDs-c(RGDyk)NP exhibited significantly lower toxicity against PC12 and C6 cells and HUVECs than free QDs. Moreover, in vitro cellular uptake experiments demonstrated that QDs-c(RGDyk)NP specifically targeted C6 cells, making them display strong fluorescence. Combined with ultrasound-targeted microbubble destruction (UTMD), QDs-c(RGDyk)NP specifically accumulated in glioma tissue in orthotropic tumour rats after intravenous administration, evidenced by ex vivo NIR fluorescence imaging of bulk brain and glioma tissue sections. Furthermore, fluorescence imaging with QDs-c(RGDyk)NP guided accurate surgical resection of glioma. Finally, the safety of QDs-c(RGDyk)NP was verified using pathological HE staining. In conclusion, QDs-c(RGDyk)NP may be a potential imaging probe for imaging-guided surgery.
Photodynamic therapy (PDT) has recently emerged as an approach to enhance intratumoral accumulation of nanoparticles. However, conventional PDT is greatly limited by the inability of the excitation light to sufficiently penetrate tissue, rendering PDT ineffective in the relatively deep tumors. To address this limitation, we developed a novel PDT platform and reported for the first time the effect of deep-tissue PDT on nanoparticle uptake in tumors. This platform employed c(RGDyK)-conjugated upconversion nanoparticles (UCNPs), which facilitate active targeting of the nanoconstruct to tumor vasculature and achieve the deep-tissue photosensitizer activation by NIR light irradiation. Results indicated that our PDT system efficiently enhanced intratumoral uptake of different nanoparticles in a deep-seated tumor model. The optimal light dose for deep-tissue PDT (34 mW/cm 2 ) was determined and the most robust permeability enhancement was achieved by administering the nanoparticles within 15 minutes following PDT treatment. Further, a two-step treatment strategy was developed and validated featuring the capability of improving the therapeutic efficacy of Doxil while simultaneously reducing its cardiotoxicity. This two-step treatment resulted in a tumor inhibition rate of 79% compared with 56% after Doxil treatment alone. These findings provide evidence in support of the clinical application of deep-tissue PDT for enhanced nano-drug delivery.
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