Targeted tumour theranostics in mice via carbon quantum dots structurally mimicking large amino acids
Authors: Yu Zhou
Shuhua Li
Miao Li
Hao Wu
Louzhen Fan
Jia Zhu
Shixin Zhou
Zeming Chen
Xingchun Gao
Fanglong Yuan
Xiaohong Li
Fuyao Liu
Xingchen Zhai
Ting Yuan
Jun Liu
Chang Yuan
Ann T Chen
Youmei Bao
Wen Su
Gang Deng
Hongwei Tan
Jiangbing Zhou
Yunchao Li
Journal: Nature Biomedical Engineering (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Strategies; imaging; delivering drugs; tumours; carbon quantum dots
Affiliations: College of Chemistry, Key Laboratories of Theoretical and Computational Photochemistry, and Radiopharmaceuticals, Ministry of Education, Beijing Normal University, Beijing, China., Department of Neurosurgery, Yale University, New Haven, CT, USA., Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China., College of Chemistry, Key Laboratories of Theoretical and Computational Photochemistry, and Radiopharmaceuticals, Ministry of Education, Beijing Normal University, Beijing, China. ., Department of Biomedical Engineering, Yale University, New Haven, CT, USA., Department of Neurosurgery, Yale University, New Haven, CT, USA. ., Department of Biomedical Engineering, Yale University, New Haven, CT, USA. .

Abstract:  Strategies for selectively imaging and delivering drugs to tumours typically leverage differentially upregulated surface molecules on cancer cells. Here, we show that intravenously injected carbon quantum dots, functionalized with multiple paired α-carboxyl and amino groups that bind to the large neutral amino acid transporter 1 (which is expressed in most tumours), selectively accumulate in human tumour xenografts in mice and in an orthotopic mouse model of human glioma. The functionalized quantum dots, which structurally mimic large amino acids and can be loaded with aromatic drugs through π-π stacking interactions, enabled-in the absence of detectable toxicity-near-infrared fluorescence and photoacoustic imaging of the tumours and a reduction in tumour burden after the targeted delivery of chemotherapeutics to the tumours. The versatility of functionalization and high tumour selectivity of the quantum dots make them broadly suitable for tumour-specific imaging and drug delivery. 

Retracted: No

PubPeer comments:
 Figure 4A * Aqua blue boxes: In the LAAM TC-CQDs row, the HeLa and A549 cells appear to show an overlap in the Red and Merge channels, if one of the panels is 90 degrees rotated, shifted a bit, and if contrast is changed. Only the  Red panels are marked. ![file] , 
 Figure S20 * Orange boxes: The HKC panels appear to show an overlap with the CCC-HIE-2 panels, if one of the two sets is rotated 90 degrees. ![file] Only the  Red panels are marked. , 
 Figure S25. * Green boxes: The 6h and 8h panels look similar. Only the red channel panels are labeled, but the other panels look similar too. Could the authors clarify how the confocal images were taken at different time points? The methods suggest that samples were taken at different time points and fixed with polyformaldehyde before the confocal microscopy image was taken. ![file] , 
 Figure S61. * Blue boxes: In the Heart row, the  Saline and the  TPTC LAAM TC-CQDs panels appear to show an overlap. ![file] , 
 Several mice in Figures 2C, Suppl 29, and Suppl 56 appear to look similar to each other, although they seem to represent different injections and or time points. In addition, some of these mice also look similar to mice shown in FIgurer 7A of an older paper by the same group, i.e. Shuhua Li et al., ACS Applied Materials Interfaces, 9(27), 22332u201322341. doi:10.1021 acsami.7b07267 - see: https: pubpeer.com publications 6A97997216628EFFF192A009E95377#1 Boxes of the same color show mice that look similar to each other. ![file] , 
 Updating the figures from comment #5 with additional findings by other readers, in particular about mice from Figure S29. ![file] , 
 #4 Another overlap in Figure S61. Yellow boxes: In the Spleen row, the  Saline and the  TPTC LAAM TC-CQDs panels. ![file] , 
 Fig. 6 | Characterization of LAAM CQDs for tumour-specific imaging and drug delivery. a,b, Molecular structures (a) and cell penetrability (b) of LAAM TC-CQDs, NH2- and COOH-null LAAM TC-CQDs, 2,6-CQDs, 1,4-CQDs and 1,5-CQDs and Phe-CQDs. Scale bar, 50 u03bcm. Yellow boxes: NH2- and COOH-null LAAM TC-CQDs treated with HeLa cells. Bule boxes: NH2-null LAAM TC-CQDs and 2,6-CQDs treated with CCC-ESF-1 cells, same scale bar but the size of cells is different. ![file] , 
 The authors responsed to Nature, yet still haven t made any sort of clarification on PubPeer. ![file] , 
 What happened to this paper? some organs and tumor (color boxes) in Figures 2e appear to look very similar to an older paper by the same group and the same first author, Shuhua Li et al., ACS Applied Materials Interfaces, 9(27), 22332u201322341. see: https: pubpeer.com publications 6A97997216628EFFF192A009E95377#2 ![file] , 
 Concerns about FigS26, as fun as a jigsaw puzzle. ![file] , 
 Several organs in Figure S30 and S38 appear to look similar to each other, although they seem to represent different injections or mice. ![file] , 
 Figure 4A Yellow boxes: In the TPTC and TPTC-LAMM TC-CQDS row, the HeLa and A549 cells appear to show an overlap, if one of the panels is 90 degrees rotated, shifted a bit, and if contrast is changed. ![file] , 
 About 20 duplicated panels, some of which were rotated or otherwise altered, and the journal issued a Correction, January 2022: https: www.nature.com articles s41551-022-00845-x  In the version of this article originally published, incorrect sets of micrographs for A549 cells in **Fig. 4a** and for the NH2-null LAAM TC-CQDs group in **Fig. 6b** were inadvertently used. The original and corrected figures are reproduced below. We were also informed of errors in a few figures in the Supplementary Information. In particular, we accidentally used a few duplicated sets of images for the RWPE-1, HL-7702, CCC-HPE-2 and CCC-HIE-2 cell lines in **Supplementary Fig. 20**, for the mice underlying the in vivo fluorescence images in **Supplementary Fig. 29** (some images were duplicated from **Supplementary Fig. 56**; in this figure, we also had selected incorrect images for the 0-h timepoint of the TPTC group and for the 6-h timepoint of the TPTC LAAM TC-CQDs), for the excised mouse organs in **Supplementary Fig. 30** (some images were duplicated from **Supplementary Fig. 38**), and for the images of the heart and the spleen in the TPTC LAAM TC-CQDs group in **Supplementary Fig. 61** (the two micrographs had overlaps with those in the saline group). The original and corrected versions of these supplementary figures are also reproduced below. All these errors occurred when selecting representative images from the large datasets of images acquired, processed and stored in the core facilities that we used. In addition, for **Supplementary Fig. 25**, we detected that we had used duplicated images for the 6-h and 8-h timepoints. As noted in the original manuscript (page 706; second column, last full paragraph), for the 8-h timepoint, u201cthe concentration of LAAM TC-CQDs in the nuclei exceeded the concentration of LAAM TC-CQDs in the cytoplasm (Supplementary Fig. 25, Supplementary Video 1)u201d; therefore, we should only have shown data up to this timepoint, and the micrographs for the 10-h timepoint should have been labelled u20188 hu2019. We also note that the middle and right sets of panels in **Supplementary Fig. 52** were mislabelled (the original and corrected figure is reproduced below), that u201c25 wt%u201d should have been u201c5 wt%u201d (Supplementary Information, section u201cSynthesis of LAAM TC-CQDu201d), and that u201cSupplementary Tab. 2u201d should have been u2018Supplementary Tab. 3u201d (Supplementary Information, page 17). All versions of the article have been corrected. (bold face mine). ,