Gram-scale synthesis of coordination polymer nanodots with renal clearance properties for cancer theranostic applications

An ultrasmall hydrodynamic diameter is a critical factor for the renal clearance of nanoparticles from the body within a reasonable timescale. However, the integration of diagnostic and therapeutic components into a single ultrasmall nanoparticle remains challenging. In this study, pH-activated nanodots (termed Fe-CPNDs) composed of coordination polymers were synthesized via a simple and scalable method based on coordination reactions among Fe3+, gallic acid and poly(vinylpyrrolidone) at ambient conditions. The Fe-CPNDs exhibited ultrasmall (5.3 nm) hydrodynamic diameters and electrically neutral surfaces. The Fe-CPNDs also exhibited pH-activatable magnetic resonance imaging contrast and outstanding photothermal performance. The features of Fe-CPNDs greatly increased the tumour-imaging sensitivity and facilitated renal clearance after injection in animal models in vivo. Magnetic resonance imaging-guided photothermal therapy using Fe-CPNDs completely suppressed tumour growth. These findings demonstrate that Fe-CPNDs constitute a new class of renal clearable nanomedicine for photothermal therapy and molecular imaging.


XAS Data analysis.
We used IFEFFIT software to calibrate the energy scale, to correct the background signal and to normalize the intensity.
In the Fourier transform magnitude of the EXAFS spectrum of Fe-CPNDs, three distinct peaks are observed representing the contributions of photoelectron scattering on the nearest shells of neighbors around the Fe atom. A strong peak in the R range between 1.5 and 2.2 Å can be attributed to photoelectron backscattering on the nearest neighbors around Fe. The second peak between 2.2 and 2.5 Å in the R range represents the contributions from more distant Fe coordination shells.
Three variable parameters for each shell of neighbors are introduced in the model: shell coordination number (N), distance (R), and Debye-Waller factor (σ 2 ). Avery good agreement between the model and experimental spectrum is found using the k range of 2.5-10.8 Å −1 , and the R range from 0.8 to 2.6 Å. The list of best fit parameters is given in Supplementary Table 1. increasing from room temperature to 188 °C at a rate of 10 o C min -1 and maintained for 1 h. The intensity of IR band at 3440 cm -1 is decreased with increasing the temperature, indicating that coordinated water molecules have been released from the Fe-CPNDs. The IR intensity change of Fe-CPNDs incubated at pH 5.0 is stronger than that of Fe-CPNDs incubated at pH 7.4, suggesting that Fe-CPNDs were degraded 1 .

FTIR characterization of CO adsorbed.
In situ FTIR spectra were taken with a Nicolet 6700 spectrometer at a resolution of 4 cm −1 . The fine powder of the Fe-CPNDs was mounted in a ceramic crucible. The sample was pretreated in Ar at 25 °C for 20 min and was then exposed to a stream of 1 vol % CO/Ar. The absorption bands centered at ca. 2175 cm -1 were assigned to CO adsorbed on Fe 3+ sites 2 . was added into a water solution (9 mL). After 1 h incubation, GA aqueous solution (1 mL, 10 mg mL -1 ) was introduced into the above reaction mixture and stirred overnight.
Large-scale Synthesis of Fe-CPNDs. PVP (3.63 g) was dissolved in water (428 mL) at room temperature under vigorous stirring. And then, FeCl 3 aqueous solution (12 mL, 100 mg mL -1 ) was added into the aqueous PVP solution. After 1 h incubation, GA aqueous solution (60 mL, 10 mg mL -1 ) was introduced into the above reaction mixture and stirred overnight. The resulting nanodots were dialyzed (MWCO = 25000) against deionized water for 24 h.
In vivo Biodistribution analysis. The nude mice bearing colorectal tumor were used to examine the in vivo biodistribution of the Fe-CPNDs. The mice were first anesthetized by an intraperitoneal injection of 10 % chloralhydrate (80 µL). A NaCl solution (0.9 wt%) containing Fe-CPNDs was then intravenous (2 mg kg -1 ) or intratumor (0.25 mg kg -1 ) injected into the mice. The mice were euthanized, and the heart, liver, spleen, lung, kidney, bladder and tumor were extracted and weighted at respectively. Blood half-life was calculated with a two exponential fit using a two-compartment mode.
Renal clearance kinetics analysis. To quantitative analysis of excreted Fe-CPNDs, the mice were first anesthetized by an intraperitoneal injection of 10 % chloralhydrate (100 µL). A NaCl solution (0.9 wt%) containing Fe-CPNDs (2 mg kg -1 ) was then intravenous injected into the mice. After that, the mice were placed in the standard metabolic cages and the urines were collected with special precaution to avoid fecal contamination at 0, 2.5, 4, 12 and 24 h post-injection, and imaged by MRI after concentration. The mice were released from sedation after two hours. The urine of untreated was collected under same conditions and employed as control samples. Fe