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Peptide-aptamer co-assembly nanocarrier for cancer therapy Yue Ma, Wenjun Li, Ziyuan Zhou, Xuan Qin, Dong-Yuan Wang, Yubo Gao, Zhiqiang Yu, Feng Yin, and Zigang Li Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.8b00903 • Publication Date (Web): 31 Jan 2019 Downloaded from http://pubs.acs.org on February 4, 2019
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Bioconjugate Chemistry
Peptide-Aptamer Co-Assembly Nanocarrier for Cancer Therapy Yue Ma, ‡a Wenjun Li, ‡a Ziyuan Zhou, ab Xuan Qin, a Dongyuan Wang, a Yubo Gao, c Zhiqiang Yu, d Feng Yin *a and Zigang Li *a State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. b Chemical Biology Laboratory for Infectious Diseases, State Key Discipline of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, 518020, China. c School of Information Engineering, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. d School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China. a
Corresponding Author *E-mail:
[email protected]; *E-mail:
[email protected].
Supporting Information Placeholder ABSTRACT: We reported methionine bis-alkylated nonapeptide Wpc as efficient siRNA vehicle previously. Herein, we report aptamer could also spontaneously co-assembly with Wpc to form uniformed nanoparticles for efficient delivery. This unique peptide-based aptamer nanocarrier showed significantly improved cell penetration and anti-proliferation effect with high biocompatibility towards various cancer cell lines.
INTRODUCTION Aptamers, also termed as "chemical antibodies," are short oligonucleotides that could evolve with SELEX (systematic evolution of ligands by exponential enrichment) technology.1-3 Owing to their specific 3D structures and unique nucleotide sequence, aptamers could specifically and potently bind to a variety of molecular targets, including small molecules,4 proteins,5 cells and tissues,6,7 and even simple metal ions8. Compared with antibodies, the low immunogenicity, high specificity and potency of aptamers have endowed them as promising drug candidates.9-12 To date, numerous aptamers were developed with the bioactivity towards inflammation, anti-tumor proliferation and so on. 13-16 For example, Janjic et al. reported RNA aptamers bind to the vascular endothelial growth factor (VEGF) for the treatment of age-related macular degeneration.1719 Tan et al. reported a DNA aptamer (XQ-2d) which displayed a specific affinity with pancreatic ductal adenocarcinomas (PDAC) tissue, suggesting that it could be a good diagnostic reagent for PDAC.6 AS1411 is one of the well-developed aptamers for cancer therapy. It could efficiently inhibit the proliferation of various human tumor cell lines including lung cancer, breast cancer and prostate cancer cell lines.20,21 This may be attribute to the special G-quadruplex structure of AS1411, which could resist nuclease degradation and render high binding affinity to the nucleolin.22-24 To improve the bioactivity of AS1411, numerous nanoparticles were utilized for the efficient cellular delivery of AS1411, such as : AS1411-GNS 25 and Apt-AuNS.26-28 Despite these successful
attempts, novel delivery vectors with high biocompatibility are still of high demand. 29 As a naturally biocompatible molecule, peptides could be utilized as efficient carriers with lower cytotoxicity and safety concerns.3039 While most of the existing peptide delivery systems require complicated modifications 40,41 or long sequence 42,43. Recently, we developed a unique siRNA-induced peptide co-assembly system as siRNA nanocarrier for potential cancer therapy.44 The methionine bis-alkylated peptide Wpc Fmoc-RRMEHRMEW, which is consists of only 9 amino acids, could spontaneously coassembly with siRNA to form uniformed nanoparticles with significantly enhanced cellular uptakes. Compared with many peptides based nucleic acid carrier, this Wpc peptide is simple and easy-synthesized. Thus, we hypothesized the Wpc based coassembly nanocarrier could be utilized for the efficient and biocompatible delivery of AS1411 (single strand aptamer) and significantly enhance its cellular penetration and bioactivity (Scheme 1). After internalized by cells, the high concentration of cytoplasmic GSH may reduce the bis-alkylation at Met to weaken the electronic interaction between peptide and nucleotide and promote the release of RNA. 44-47 As we hypothesized, peptide Wpc could spontaneously co-assembly with AS1411 to form uniform nanoparticles at first. AFM, SEM, DLS (Dynamic light scattering) and Zeta potential characterization displayed a uniform nanoparticle with diameters of ~100nm. In the flow cytometry analysis and confocal microscopy imaging, this peptide-AS1411 co-assembly nanoparticles could achieve efficient cell penetration in various cell lines (T47D cells, HeLa cells and Chang liver cells). Besides, both the light field imaging and MTT assay showed that peptide- AS1411 co-assembly nanoparticles could achieve significant growth inhibition of T47D cells and HeLa cells. While for normal cell lines (Chang liver cells and QSG7701 cells), this AS1411 induced co-assembly nanocarrier showed only negligible cytotoxicity. Further exploration of cell death by flow cytometry displayed that the peptide-AS1411 co-assembly nanoparticles could efficiently induce cell cycle arrest and apoptosis. These results demonstrated that this peptide-aptamer (AS1411) co-assembly nanoparticle could be utilized as an efficient AS1411 nanocarrier with significantly improved cellular uptake and anti-growth inhibition towards various cancer cells.
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Scheme 1. Schematic presentation of this novel peptide-aptamer (AS1411) co-assembly nanoparticle with improved cellular uptake and anti-growth inhibition towards various cancer cells.
RESULTS AND DISCUSSION The Wpc peptide was prepared as previous report.44 The ratio of Wpc peptide and aptamer (AS1411) was determined by the gel retardation assay shown in Figure S1. 1.0μg AS1411 could be fully loaded with 30μg Wpc peptide (the N/P ratio is about 12). This ratio was utilized in the following experiments. The sequences of AS1411, scramble and Wpc peptide utilized in this research are summarized in Table S1. Characterizations of peptide-AS1411 complex were further conducted. Both AFM and SEM images showed a uniformed nanoparticle formation with ~100nm diameter (Figure 1A, B and S2). While the Free AS1411 and Wpc peptide displayed amorphous forms (Figure S2). The Dynamic light scattering (DLS) analysis showed the hydrodynamic diameter of the peptide-AS1411nanoparticle to be ~137.7nm (Figure 1C). Furthermore, Zeta potential of peptide-AS1411 complex showed a significant increase comparing with AS1411 itself (Figure 1D). These results demonstrated that peptide Wpc could readily coassembly with AS1411 to form uniform nanoparticles with ~100nm diameter. To further investigate the stability of peptideAS1411 co-assembly nanoparticles, the nanoparticles were incubated with cell lysate (5mg/ml) and DNA enzyme (1mg/ml) at 37oC for 5h. And the
Figure 1. Characterizations of Wpc nanoparticles. (A) AFM imagine of nanoparticles. (B) SEM imagine of
peptide-AS1411 peptide-AS1411 peptide-AS1411
nanoparticles. (C) DLS analysis of peptide-AS1411 nanoparticles. (D) Zeta potential analysis of peptide-AS1411 nanoparticles. data from SEM image showed negligible changes in size and structure (Figure S3). These results indicated that this peptideAS1411co-assembled nanoparticle might be satisfyingly stable in protein rich and DNA enzyme conditions. Flow cytometry assay was further performed for the evaluation of the nanoparticles’ cellular uptakes with Lipo-2000 or Oligo as positive controls. Both the median fluorescent intensity (MFI) and transfection efficiency showed a significantly increased cellular uptake of AS1411 nanoparticles in T47D cells (human breast cancer cell line) (Figure 2A and B). Confocal laser scanning microscopy (CLSM) was further utilized to confirm the cellular internalization of peptide-AS1411 nanoparticles. As shown in Figure 2C, weak fluorescent signals were observed from the free AS1411FAM and AS1411FAM with Lipo-2000 and Oligo. Whereas, strong and homogeneously distributed fluorescence was observed from the whole cells transfected with peptide-AS1411FAM nanoparticles. In addition, the peptide-AS1411 FAM complex also showed significantly enhanced and homogeneously distributed fluorescence in HeLa cells (Figure S4), Chang liver cells (Figure S5) and QSG7701 cells (Figure S6). Notably, the free AS1411 could also achieve cell penetration at high concentration of approximately 10μM.25,27 Very limited uptakes of AS1411 were detected with both flow cytometry assay and confocal microscopy imaging at 0.25μM (1.0μg AS1411 diluted in 500ul medium). These results demonstrated that peptide-AS1411 nanoparticles could efficiently improve the cellular uptake of AS1411 in various cell lines. Further investigation of the potential mechanism of the internalization of nanoparticles was also conducted. As shown in Figure S7, Nystatin (endocytic inhibitor), low temperature treatment and NaN3 + 2-Deoxy-D-glucose (ATP inhibitor) could reduce the cellular uptake of nanoparticles in T47D cells, while Amiloride (macropinocytosis inhibitor) has little effect on nanoparticles’ cellular uptake These results indicated that endocytosis mechanism was important for the cell penetration of peptide-AS1411 co-assembled nanoparticles. As the improvement of cellular uptake may increase the efficiency of AS1411.25,27 Thus, MTT assay was further conducted to evaluate the growth inhibition of peptide-AS1411 nanoparticles in cancer cell lines. As shown in Figure 3A and 3B, an efficient growth inhibition was observed in T47D cells and HeLa cells. While for non-malignant cell lines such as Chang liver cells and
Figure 2. Cellular uptake evaluation of peptide-AS1411 nanoparticles in T47D cells. (A-B) Median fluorescent intensity (MFI) and transfection efficiency analysis of peptideAS1411FAM/nanoparticles in T47D cells. (C) Confocal microscopy imaging of free AS1411FAM, peptide-AS1411FAM nanoparticles, Lipo-2000 with AS1411FAM and Oligo with AS1411FAM (40X). The imaging of peptide-AS1411FAM nanoparticles showed a significantly enhanced fluorescence. The scale bars are 20μm. The concentration of utilized AS1411FAM
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Bioconjugate Chemistry was 1.0μg with 30μg peptides incubated in 500ul medium for 10min at room temperature, then incubated with the cells for 4 hours in 37℃, 5% CO2 incubator.
and activate the anti-growth inhibition effect of different cancer cells. Furthermore, apoptosis progress of the HeLa cells was further
Figure 3. Cell viability assay and cell cycle distribution of peptide-AS1411 nanoparticles. Graphs showing the effect of different concentrations of peptide-AS1411 co-assembly nanoparticles on the growth of T47D cells (A) and HeLa cells (B), normal cell lines Chang liver cells (C) and QSG7701 cells (D). The peptide-AS1411 co-assembly nanoparticles showed an improved anti-proliferation effect for both T47D cells and HeLa cells. Error bars represent SEMs of at least three independent measurements. (E-F) The cell cycle distribution analysis of HeLa cells and T47D cells was determined through PI staining and flow cytometry analysis. A clearly higher proportion of S phase could be observed in both T47D cells and HeLa cells treated with (1.0μg AS1411 with 30μg peptide) nanoparticles than blank and negative controls.
evaluated as shown in Figure 4A. Compared with free AS1411 (1μg), a clear increase of apoptosis was observed in HeLa cells Figure 4. Peptide-AS1411 co-assembled nanoparticles efficiently induce the apoptosis in HeLa cells. (A) HeLa cells were treated with peptide-AS1411 nanoparticles (1.0μg AS1411 with 30μg peptide) and free AS1411 (1.0μg) for 72 h, then HeLa cells were stained with Annexin V/PI and the number of apoptotic cells was measured by flow cytometry. (B) Apoptotic cells count in the lower right (Q2) and upper right (Q3) for different treatment groups. The apoptotic cells of each analysis were calculated and normalized to blank. Error bars represent the standard error of mean from three independent experiments.
QSG7701 cells, this co-assembled nanocarrier displayed negligible cytotoxicity at the concentration tested (Figure 3C and D). For T47D and Hela cells, the GI50 (concentration required to inhibit cell growth by 50%) of peptide-AS1411 nanoparticles was about 2.0μg/ml, which was significantly improved from AS1411 itself. Blood toxicity assays of peptide-AS1411 nanoparticles was performed with fresh mouse blood cells and only negligible toxicity was observed (Figure S8 and S9). Bright-field images showed consistent results as MTT assays and the blood toxicity assays. (Figure S10) To further investigate the death of cancer cells caused by peptide-AS1411 nanoparticles, cell cycle arrestment analysis was further conducted. We found that both the complex (peptideAS1411 nanoparticles) and AS1411 delivered by positive controls (Lipo-2000 and Oligo) showed a clear S phase cycle arrest in HeLa cells and T47D cells (Figure 3E, F and S11). Notably, the free AS1411 could also achieve the anti-growth inhibition and cell cycle arrest at high concentration about 10μM.48 While, as our goal is to find a powerful and biocompatible nanocarrier for efficient and safe AS1411 delivery, thus, the concentration of AS1411 utilized in MTT assay, cell cycle and apoptosis assay are only 1μM, which is enough to efficiently transfect into cytoplasm
treated with peptide-AS1411 complex. Peptide-AS1411 complex could induce over 75% apoptosis of Hela cells, more effective than transfection reagent Lipo-2000 and Oligo (Figure 4B). Similar results were also observed with T47D cells Figure S12. CONCLUSION In summary, Wpc could spontaneous co-assembly with aptamer and form uniform nanocarrier, which was characterized by AFM, SEM, DLS and Zeta potential analysis. And this unique AS1411 nanocarrier displayed significantly enhanced cellular uptake in various cell lines, which was identified by flow cytometry and confocal microscopy imaging. Besides, this nanocarrier showed selective cytotoxicity towards cancer cells and negligible cytotoxicity towards normal cells. Furthermore, this nanocarrier could induced efficient apoptosis and showed clear S phase cycle in both HeLa cells and T47D cells. Compared to the conventional delivery system, this Wpc-based nanocarrier with simpler production process, high biocompatibility and enhanced cell permeability could achieve efficient anti-proliferation effect towards various cancer cells. Shangguan et al. reported that AS1411 could be degraded in serum and the release of high concentration of guanine might show non-selective toxicity towards cells.49 Thus, a biocompatible and efficient delivery system may be important for AS1411 or
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alike aptamers. Taking its excellent transfection efficiency into consideration, this system could be optimized for further therapeutic development, which is under current investigation in our laboratory. We believe with the optimizations of sequence and modifications, this AS1411 based nanocarrier could be further utilized for the anti-growth inhibition and therapeutic treatment of tumor cells.
ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Additional details on materials and methods. Figures showing Gel retardations, SEM image, blood toxicity, bright field images, experimental results. Tables showing AS1411, scramble and peptide sequences.
AUTHOR INFORMATION Corresponding Author *E-mail:
[email protected]; *E-mail:
[email protected].
Author Contributions ‡ These authors contributed equally to this work.
Notes The authors declare no competing financial interests.
ACKNOWLEDGMENT We acknowledge support for this work from the Natural Science Foundation of China grants 21778009 ， 81701818 and 81572198; the Shenzhen Science and Technology Innovation Committee, JCYJ20170807144449135, KQJSCX20170728101942700 and JCYJ20170412150609690.
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