Molecularly Engineered Aptamers Targeting Tumor Tissue and Cancer Cells for Efficient in Vivo Recognition and Enrichment

Open AccessCCS ChemistryCOMMUNICATION5 Aug 2022Molecularly Engineered Aptamers Targeting Tumor Tissue and Cancer Cells for Efficient in Vivo Recognition and Enrichment Xia Wang, Xiao-Jing Zhang, Yingying Li, Guo-Rong Zhang, Juan Li, Xue-Qiang Wang and Weihong Tan Xia Wang Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082 , Xiao-Jing Zhang Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082 , Yingying Li Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082 , Guo-Rong Zhang Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082 , Juan Li The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022 , Xue-Qiang Wang *Corresponding author: E-mail Address: [email protected] Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082 Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, Hunan University, Changsha, Hunan 410082 and Weihong Tan Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082 Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, Hunan University, Changsha, Hunan 410082 Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200127 https://doi.org/10.31635/ccschem.021.202101337 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Molecular engineering of aptamers can confer exogenous biomedical properties that may be beneficial for various applications. In this study, a tumor-homing peptide modification strategy was developed to considerably enhance the accumulation and penetration abilities of the Sgc8c aptamer. Notably, the S2PM conjugate induced a much higher level of morphological variation in three-dimensional tumor microspheres (HCT116 cells) than in control groups, highlighting the importance of the homing and penetrating abilities derived from peptide. Moreover, the S2P accumulated at the tumor sites in a more selective manner in both HCT116 and 4T1 tumor models and was retained at the tumor sites for a much longer time than the control groups. These findings indicate that this newly developed molecular engineering strategy has great application potential in aptamer-mediated drug delivery. Download figure Download PowerPoint Introduction The field of precision medicine has advanced considerably in recent years, mainly attributed to an overall better understanding of the occurrence and pathogenesis of cancers.1,2 Despite the powerful potential of this technology, its translation in clinical oncology is problematic due to several challenges, including drug resistance and severe side effects caused by the high toxicity of anticancer drugs.3–8 To mitigate these problems, various targeted drug delivery strategies have been established with targeting ligands ranging from small molecules9–11 to peptides,12,13 antibody fragments,14–17 protein scaffolds,18 and intact antibodies,19–22 thus allowing the modulation of the pharmacological properties of anticancer drugs. The success of these drug delivery strategies relies on enhancing location precision (tissue or organ-specificity) and drug delivery timing (controlled drug release). Aptamers have recently been utilized as vehicles to selectively transport various anticancer agents and improve therapeutic outcomes, owing to their high specificity, high affinity, broad targeting ability, and low immunogenicity.23 This approach overcomes the disadvantages of small molecule drugs, such as unwanted toxicity.24–37 However, previous studies have not been focused enough to enhance the tumor tissue enrichment and penetration abilities of aptamer-drug conjugates (ApDCs) sufficiently, so as to significantly improve their anticancer efficacy.30 The tumor microenvironment (TM) plays a crucial role in tumor growth and metastasis.38–40 The extracellular matrix, which is composed of collagen, proteoglycan, laminin, and fibronectin, is the main component of the TM. Fibronectin is overexpressed in tumor tissues, especially in metastatic tissues, and binds to receptors on the surface of tumor cells, which is closely related to the facilitation of tumor invasion and metastasis.41 Over the past few decades, fibronectin has been widely used as a target in the detection, imaging, and treatment of various cancers.42,43 We hypothesized that the accumulation of aptamers in solid tumors could be significantly enhanced by taking advantage of the TM as a targeting location, thereby achieving efficient drug delivery. Herein, we report the first example of regulating aptamer accumulation at tumor tissue via a tumor-homing peptide modification approach (Figure 1a). Figure 1 | Conjugate design and binding ability analysis. (a) Structure of Sgc8c-peptide conjugates. (b) Western blot analysis and (c) quantitative analysis of the PTK7 expression level in different cells. (d) Flow cytometry analysis of the binding ability of Cy5-Sgc8c, SP, S2P, Con, and CP against HCT116, 4T1, and K562 cells (treatment with 20 nM of samples in binding buffer for 30 min at 4°C). Download figure Download PowerPoint Results and Discussion Our investigation began with the preparation of aptamer-peptide conjugates using a protein tyrosine kinase 7 (PTK7)-targeting aptamer (Sgc8c) and a tumor-homing peptide, Cys-Arg-Glu-Lys-Ala (CREKA44–46), which binds specifically to fibronectin in the tumor extracellular matrix. Cy5-Sgc8c-CREKA (SP) and Cy5-Sgc8c-(CREKA)2 (S2P) were first synthesized by a one-step metal-free click reaction of Cy5-labeled Sgc8c-dibenzocyclooctyne (DBCO) group with CREKA-azide in 95% isolated yields (Figure 1a and Supporting Information Figures S1–S3 and S8). HCT116 (a colorectal cancer cell line representing a metastatic solid tumor that easily spreads to the liver, esophagus, and other organs) and 4T1 cells (a highly transferable mouse breast cancer cell line) were selected to identify the recognition ability of the prepared conjugates. Western blot experiments showed that PTK7 was overexpressed on the membranes of HCT116 and 4T1 cells (Figures 1b and 1c), but not in the control K562 cells (a human myelogenous leukemia cell line). Binding capacity assays were conducted using flow cytometry (Figure 1d). SP (dark green) and S2P (light brown) showed a comparable binding ability to Sgc8c (green) in both HCT116 and 4T1 cells, whereas no binding to K562 cells was observed in any groups. As an additional investigation of the tumor binding function of conjugates, we labeled Sgc8c with Cy5 and CREKA with 5-carboxyfluorescein (5-FAM) to produce a Cy5-Sgc8c-FAM-CREKA conjugate for two-channel flow cytometry assays ( Supporting Information Figure S9). As expected, Cy5 and FAM fluorescence signals were detected, thus indicating that the peptide modification of Sgc8c did not affect its recognition function. Notably, the control groups, Con (explicit sequence) and CP (control sequence-peptide conjugate), did not show any binding tendency toward the three experimental cell lines. The internalization ability of SP and S2P was evaluated using confocal imaging experiments with Cy5-Sgc8c and CP as the control groups (Figure 2a). The red Cy5 channel of Sgc8c, SP, and S2P overlaid well with LysoTracker Green in HCT116 cells, while the CP control group exhibited negligible internalization events. Additional confirmation of the uptake of Sgc8, SP, S2P, and CP by HCT116 cells was provided by the results of the time-dependent flow cytometry analysis, which compared the Cy5 fluorescence intensity of the different conjugates (Figure 2b). The endocytic fluorescence density of SP and S2P increased with time, and the total density was not significantly different from that of Cy5-Sgc8c. As expected, CP showed inconspicuous internalization tendency over time. Confocal imaging of Cy5-Sgc8c, SP, S2P, and CP groups uptake in 4T1 cells indicated the same trend ( Supporting Information Figure S10). Figure 2 | Determination of uptake of the prepared conjugates. Cellular internalization assays. (a) Confocal imaging of HCT116 cells treated with 500 nM Cy5-Sgc8c, SP, S2P, and CP for 2 h at 37 °C. Scale bar: 50 μm. (b) Flow cytometry analysis of time-dependent endocytosis following treatment with Cy5-Sgc8c, SP, S2P, or CP at 500 nM. Red channel: Cy5. Download figure Download PowerPoint Next, a three-dimensional (3D) multicellular tumor microsphere model was used to study the penetration ability of SP and S2P in metastatic solid tumor tissue (Figure 3a). HCT116 multicellular tumor microspheres were incubated separately with Cy5-Sgc8c, SP, S2P, or CP for 2 h at 37 °C. The average fluorescence intensities of SP and S2P were 3.1- and 4.2-fold higher, respectively, than those of Cy5-Sgc8c (Figure 3b), whereas CP had almost no penetration ability in this model (Figure 3c). We were also interested in establishing whether the high penetration ability of SP and S2P could be retained when they were incubated with more aggressive 4T1 cells. A similar trend in fluorescence intensity was observed in the 4T1 multicellular tumor microsphere model ( Supporting Information Figure S11). These results suggested that this tumor-homing CREKA peptide modification strategy could significantly enhance the accumulation and penetration abilities of aptamers in different types of tumors. Figure 3 | The penetration ability of conjugates in 3D HCT116 tumor cells spheres. (a) Confocal images at intervals of 20 μm from the top to the middle section of HCT116 tumor spheroids, incubated with 500 nM Cy5-Sgc8c, SP, S2P, and CP; scale bar: 100 μm. (b) Normalized mean fluorescence density of Cy5 in the different conjugates shown in (a). (c) The 3D quantization graph curve of the maximum intensity of the Cy5 channel in (a). Download figure Download PowerPoint We next investigated our hypothesis by evaluating the tumor-targeting Sgc8c-CREKA system as a selective anticancer drug delivery vehicle. To this end, we first coupled mitomycin C (MMC) onto SP, S2P, CP, and CREKA via disulfide bond linker chemistry (controlled MMC release with glutathione) to prepare the corresponding aptamer-peptide-drug conjugates, namely SPM, S2PM, CPM, and PM (Figure 4a; for preparation details, see Supporting Information Schemes S1 and S2 and Figures S4–S7). The cytotoxicity of these conjugates was determined using the 72-h Cell Counting Kit-8 (CCK-8) assay. S2PM (IC50: 83.7 nM) exhibited similar inhibition efficiency to MMC (IC50: 95.2 nM) against HCT116 cells, while SPM (IC50: 276 nM) and S2P1M (IC50: 173 nM) were less cytotoxic (Figures 4b and 4c). The control groups, CPM and PM, showed much lower cancer-killing ability. We also compared the cytotoxicity of the prepared conjugates against 4T1 cells, and S2PM exhibited the highest cell apoptosis-inducing ability ( Supporting Information Figure S12). Cell apoptosis induced by SPM, S2PM, and MMC was detected by flow cytometry and confocal imaging technologies (48 h incubation; Supporting Information Figures S13–S16). The cell cycle arrest experiments showed that both SPM and S2PM inhibited the cell cycle in the G2/M phase, similar to MMC (Figure 4d). These data suggested that SPM and S2PM entered the cells and released MMC to cause death. Figure 4 | Cytotoxicity assays of Sgc8c-CREKA- MMC conjugates. (a) Structure of the conjugates. (b) Cytotoxicity and (c) IC50 values of SPM, S2PM, S2P1M, CPM, PM, and MMC against HCT116 cells in a 72-h CCK-8 assay. (d) The cell cycle of HCT116 cells treated with different conjugates (800 nM). All data are presented as the mean ± standard error of the mean (n = 3); purple: G0/G1 stage, yellow: S stage, green: G2/M stage. (e) Morphological changes in the 3D tumor microspheres following treatment with Sgc8c-CREKA-MMC conjugates or RPMI 1640 culture medium (control) for 0, 1, 2, 3, and 4 days (scale bar: 200 μm). Download figure Download PowerPoint Additional investigation of our tumor-homing peptide modification strategy focused on the morphological changes in 3D tumor microspheres during incubation with different conjugates at 37 °C. We hypothesized that S2PM and SPM would cause more cell apoptosis and more obvious morphological changes because of their notable homing and deep penetration abilities. Indeed, S2PM caused much higher morphological variation in HCT116 cell microspheres than MMC (Figure 4e), and stopped cancer cell proliferation. Furthermore, SPM displayed superior anticancer activity compared with MMC. Unsurprisingly, 1640 medium, PM, and CPM groups had little effect in the HCT116 cell microspheres. We next utilized an experimental wound-healing model to study the inhibitory effect of SPM and S2PM on cell migration using CPM, PM, and MMC as control groups ( Supporting Information Figure S17). S2PM showed the highest efficiency at preventing cell migration (based on the percentage of healing in HCT116 cells). It is worth noting that SPM had a better capacity to inhibit cell migration although the cytotoxicity of MMC was slightly higher than that of SPM. These observations demonstrated the advantage of our newly designed CREKA peptide modification technique. After obtaining encouraging in vitro results, we subsequently explored the potential of utilizing SP and S2P conjugates for efficient in vivo targeted drug delivery. Cy5-Sgc8c, CP, SP, and S2P were injected into BALB/c nude mice bearing metastatic HCT116 cells, followed by a caudal vein injection protocol. HCT116 and 4T1 cells were grown as xenografted tumors in mice, and images were obtained using an in vivo imaging system at different time points ranging from 0.5 to 8 h after treatment (Figure 5 and Supporting Information Figures S18 and S19). All the tested conjugates rapidly accumulated at the tumor sites (1 h), and the fluorescence signal of CP disappeared after 2 h in both tumor models. After 2 h, only a slight amount of Cy5-Sgc8c was recorded in mice with HCT116 cell tumors (Figure 5a), whereas no Cy5-Sgc8c accumulation was observed in 4T1 tumor-bearing mice (Figure 5b). In sharp contrast, the SP-treated group showed much higher fluorescence intensity at the tumor site after 2 h, and persisted up to 8-h posttreatment (Figure 5). More importantly, S2P, which possesses two CREKA peptide moieties, displayed the highest fluorescence intensity at the tumor sites compared with the other three samples in both xenograft mouse models. Figure 5 | In vivo selective accumulation of the conjugates at the tumor site (circled with red dashed line). (a) HCT116 cell xenograft mice and (b) 4T1 cell xenograft mice. Download figure Download PowerPoint In addition, we conducted tumor tissue slice analysis to determine the accumulation and penetration abilities of the conjugates ( Supporting Information Figure S20). The fluorescence intensity was highest in the tumor tissue of the S2P-treated group, where co-localization imaging using the Cy5 signal and fluorescein isothiocyanate (FITC)-labeled fibronectin showed that the majority of the SP and S2P was distributed around or overlapped with fibronectin. These outcomes indicated that the modification of aptamers with tumor-homing peptides could significantly enhance their selective accumulation and penetration capabilities, thus conferring them with efficiently targeted drug delivery functions. Conclusions We developed a tumor-homing peptide modification technique with the aim of enhancing the selective accumulation and deep penetration abilities of aptamers in metastatic tumors. Specifically, we efficiently prepared Sgc8c-CREKA conjugates, SP and S2P. These two conjugates were able to specifically recognize and enter the target HCT116 and 4T1 cells as the parent Sgc8c aptamer. Subsequent experiments in 3D multicellular tumor microspheres showed that peptide modification significantly enhanced the penetration ability of aptamers, which suggests its great potential for efficient targeted drug delivery. To explore this potential, we conjugated SP and S2P with MMC to produce SPM and S2PM. We found that both SPM and S2PM induced the highest level of morphological variation in 3D tumor microspheres, indicating the importance of enhanced targeting and penetrating abilities in anticancer drug delivery. The in vivo imaging experiments using xenograft mice (HCT116 and 4T1 models) demonstrated that SP and S2P accumulated at the tumor sites in a much more selective manner, and persisted at the target sites for a much longer time. Based on our findings, we believe that this newly developed tumor-homing peptide modification strategy would advance the application of aptamers in targeted drug delivery considerably. Supporting Information Supporting Information is available and includes conjugates preparation, their characterization, details of cell-related experiments and animal-related experiments, and sequence of DNA ( Supporting Information Table S1). Conflict of Interest The authors declare no competing financial interest. Disclosures All procedures related to animals were performed in accordance with the Committee on Animals guidelines of the Hunan University. Funding Information This work is supported by the National Key R&D Program of China (no. 2018YFA0902300), the Huxiang Young Talent Program from Hunan Province (no. 2019RS2022), the National Natural Science Foundation of China (no. 91959102), and Postgraduate Research and Innovation Project from Hunan Province (no. CX20190269). References 1. Dugger S. A.; Platt A.; Goldstein D. B.Drug Development in the Era of Precision Medicine.Nat. Rev. Drug Discov.2018, 17, 183–196. Google Scholar 2. Ashley E. A.Towards Precision Medicine.Nat. Rev. Genet.2016, 17, 507–522. Google Scholar 3. Kimmelman J.; Tannock I.The Paradox of Precision Medicine.Nat. Rev. Clin. Oncol.2018, 15, 341–342. Google Scholar 4. Zitvogel L.; Apetoh L.; Ghiringhelli F.; Kroemer G.Immunological Aspects of Cancer Chemotherapy.Nat. Rev. Immunol.2008, 8, 59–73. Google Scholar 5. Chen H. X.; Cleck J. N.Adverse Effects of Anticancer Agents that Target the VEGF Pathway.Nat. Rev. Clin. Oncol.2009, 6, 465–477. Google Scholar 6. 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