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Endogenous ROS-Triggered Morphology Transformation for Enhanced Cooperative Interaction with Mitochondria Dong-Bing Cheng, Xue-Hao Zhang, Yu-Juan Gao, Lei Ji, Dayong Hou, Ziqi Wang, Wanhai Xu, Zeng-Ying Qiao, and Hao Wang J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07727 • Publication Date (Web): 22 Apr 2019 Downloaded from http://pubs.acs.org on April 23, 2019
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Journal of the American Chemical Society
Endogenous ROS-Triggered Morphology Transformation for Enhanced Cooperative Interaction with Mitochondria Dong-Bing Cheng1, Xue-Hao Zhang1, Yu-Juan Gao1, Lei Ji1, Dayong Hou2, Ziqi Wang2, Wanhai Xu2, Zeng-Ying Qiao1*, Hao Wang1* 1CAS
Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, China 2Department
of Urology, the Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin, 150001, China. Supporting Information ABSTRACT: The morphology controlled molecular assemblies
play vital roles in biological systems. Here we present endogenous reactive oxygen species (ROS)-triggered morphology transformation of polymer-peptide conjugates (PPCs) for cooperative interaction with mitochondria, exhibiting high tumor therapeutic efficacy. The PPCs are composed of i) a β-sheet-forming peptide KLVFF conjugated with poly (ethylene glycol) through ROS-cleavable thioketal, ii) a mitochondriatargeting cytotoxic peptide KLAK and iii) a polyvinyl alcohol backbone. The self-assembled PPCs nanoparticles can enter cells and target to mitochondria. Because of over-generated ROS around mitochondria in most cancer cells, the thioketal linker can be cleaved, leading to transformation from nanoparticles to fibrous nanostructures. As a result, the locational nanofibers with exposure of KLAK exhibit enhanced multivalent cooperative interactions with mitochondria, which causes selective cytotoxicity against cancer cells and powerful tumor suppression efficacy in vivo. As the first example of ROStriggered intracellular transformation, the locational assembly strategy in vivo may provide a new insight for disease diagnosis and therapy through enhanced interaction with targeting site.
situ constructed peptide-based self-assemblies in tumor or infectious sites , which showed assembly/aggregation-induced retention (AIR) effect and enhanced the biological function of nanomaterials.10-12 Inspired by this strategy, we hypothesize an organelle-located morphology transformation (OLMT) platform to construct the fibrous nanomaterials around the mitochondria for enhancing multivalent cooperative interactions, which may improve their biological performance. Reactive oxygen species (ROS) is over-generated around mitochondria in most cancer cells.13-15 ROS-responsive chemical bonds have been introduced into drug delivery system,16, 17 which can also be used for realizing OLMT. Herein, β-sheetforming peptide KLVFF tethered with hydrophilic poly (ethylene
Scheme 1. Synthetic route of ROS-sensitive PPCs and mitochondria locational morphology transformation
Advanced drug-delivery system can protect drug from the reticuloendothelial system (RES) clearance and accumulate at disease sites through targeting effect.1-4 Extensive efforts have been paid to realize the controlled release of drugs, however limited therapeutic effect is still a main bottleneck problem for clinical translation. One of the possible reasons is the weak interaction between drug and their pharmaceutical targets.5, 6 Compared to the small molecules, the nanoassemblies exhibit different physical attributes, including size effect and multivalent binding ability, which may enhance the interaction between drugs and their targets.7 Thus it is necessary to develop position-specific assembly strategy for potential bio-effect improvement. Recently, “in vivo self-assembly” has been demonstrated to be a promising biotechnique for disease diagnostics and therapeutics.8 For instance, a precursor for producing a taxol assembly without compromising activity was reported, which could be employed for tumor targeted therapy.9 Our group in
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glycol) (mPEG) via ROS-cleavable thioketal bond (R1, sequence: CGGGKLVFF-tk-PEG) and the mitochondria-targeting cytotoxic peptide (KLAK, sequence: CGGG(KLAKLAK)2) are coupled to poly(vinyl alcohol) (PVA) by efficient thiol-ene reaction, and the resultant polymer-peptide conjugates (PPCs) can self-assemble into nanoparticles (Scheme 1). Under the assistance of KLAK, the nanoparticles reach the mitochondria, and the hydrophilic PEG shell is removed from PPCs due to the cleavage of thioketal under over-generated ROS. The breakage of hydrophilic/hydrophobic balance induces the transformation into nanofibers, which exhibits multivalent cooperative interaction and resultant enhanced destructiveness to mitochondria. This OLMT platform achieves a higher therapeutic efficacy compared to the unchanged nanosystem, offering a fundamental understanding of the relationship between the morphology of nanomaterials and their biofunction. The thioketal linker is conjugated with mPEG and further reacted with succinic anhydride to obtain mPEG-tk-COOH. Functional sequence R1 is prepared using standard Fmoc solidphase peptide synthesis method and purified by reverse-phase high-performance liquid chromatography (Scheme S1 and Figure S1- S3). Finally, P1 is synthesized by coupling KLAK and R1 to acrylated PVA (Figure S4)18 backbone, which is confirmed by the complete disappearance of the acrylate signals and the appearance of KLAK and R1 signals in 1H NMR spectra. (Scheme S2 and Figure S9). The control PPCs, including P2 (PPC without β-sheet-forming peptide), P3 (ROS-nonsensitive PPC) and P4 (PPC without PEG) are synthesized by the similar methods (Figure S5-S9). P1 can self-assemble into nanoparticles of 43.5±2.1 nm in phosphate buffer (PB) solution (Figure 1A), which are also stable
Figure 1. (A) Schematic illustrations of morphology transformation of P1 induced by ROS, and representative TEM images of P1 nanoparticles (0.2 mg mL-1) after immersed in PB solution (10 mM, pH 7.4) containing 100 μM H2O2 for 8 h. (B) ThT fluorescence of P1 (0.2 mg mL-1) after adding 100 μM H2O2 for various time scales in PB solution (10 mM, pH 7.4). (C) FTIR spectra of P1 in a spherical state and treated with H2O2 in a fibrous assembled state.
at both neutral and acidic pH (Figure S10 and S11). After incubated with 100 μM H2O2 for 8 h, P1 nanoparticles transform into fibrous nanostructure with a diameter of 11 nm, and the morphology is similar to P4 (Figure S12), implying the cleavage of PEG shell. The similar transformation is also observed in phosphate buffer saline (PBS, Figure S13). The structure change of PPCs is further confirmed by dynamic light scattering (DLS) (Figure S14 and S15). For studying the relationship between morphology transformation and chemical structure change, the ROS responsiveness of PPCs is validated by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDITOF). The thioketal in P1 can be cleaved in H2O2 to generate residue CGGGKLVFF-SH19, 20 (Figure S16 and S17). Although the PEG can be removed from P2 that becomes slightly bigger due to hydrophobicity increase, P2 remains the spherical morphology. It can be attributed to the KAAGG instead of KLVFF, which cannot form β-sheet structure21 (Figure S18). In order to explore the chemical driving force during nanofiber formation, the secondary structure of P1 is first investigated by circular dichroism (CD) (Figure S19), suggesting the formation of typical β-sheet structure. The fluorescence increase of Thioflavin T (ThT, a fluorescent probe that can selectively bind to amyloid deposits22, 23) further demonstrates the β-sheet conformation (Figure 1B). Fourier transform infrared spectroscopy (FTIR) and wide-angle X-ray scattering (WAXS) are employed for analyzing the molecular arrangement mode. The peaks at 1630 cm-1 and 1697 cm-1 in FTIR suggest the antiparallel β-sheet conformation (Figure 1C)24, 25. The WAXS gives d-spacings of 4.6 Å and 10.8 Å (Figure S20), which are attributed to the spacing of the adjacent strands and laminates, respectively.24 Thus, according to the molecular arrangement mode (Figure S20), the computational diameter of P1 nanofiber is 10.2 nm, which is in accordance with the TEM result (11 nm). In order to clarify the influence of morphology on their biological function, Cy5 labeled PPCs with red fluorescence are
Figure 2. CLSM images (A) and corresponding colocalization analysis (B) of HeLa cells treated with P1 (10 μM for KLAK) for 8 h, Cy5 (red): 633 nm, Mitotracker (green): 488 nm. Scale bar: 5 μm. (C) The SEM imaging of isolated mitochondria treated with fibrous P1 (10 μM for KLAK) for 2 h. The red arrows indicate the nanofibers. Scale bar: 200 nm.
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Journal of the American Chemical Society synthesized for tracking their localization in cells. Observed by confocal laser scanning microscopy (CLSM), the PPC nanoparticles enter cells through endocytosis and escape from lysosomes (Figure S21), followed by localization with mitochondria, owing to mitochondria-targeting peptide KLAK (Figure S22). The red fluorescence from P1 can overlap well with the green fluorescence from mitochondria, showing higher pearson’s correlation coefficient (PCC) of 0.88 than that of P2 (PCC = 0.75) and P3 (PCC = 0.73) (Figure 2A, 2B and S23). We speculate P1 nanoparticles transform into fibrous nanostructure at the mitochondria due to over-generated ROS (Figure S24), which enhances the interaction between P1 and mitochondria. Both SEM and Bio-TEM images (Figure 2C, S25 and S26) demonstrate the nanofibers can entangle the mitochondria, whereas the nanoparticles cannot attach on the mitochondria. Energy-dispersive X-ray spectroscopy (EDS) further confirms the nanofibers derive from P1. It is known that KLAK can interact with mitochondrial membrane via electrostatic and hydrophobic interaction.26 The Hill plot, which can reflect the multiple binding patterns, is introduced to describe interaction mode between PPCs and mitochondria.27-29 As shown in Figure 3A and S27, the job plot analysis of fluorescent intensity versus concentration fits well with Hill plot and the dissociation constant KD shows no significant difference among the four groups. For P1 nanofibers, the Hill coefficient toward mitochondria is 8.1. Compared to control nanoparticles (P2 and P3) and free KLAK, the higher Hill coefficient suggests stronger multivalent cooperative interactions and higher binding affinity between nanofibers and mitochondrial membrane (Figure 3C). Obviously, the fibrous nanostructures possess larger contact area and more interaction sites with the mitochondrial membrane than nanoparticles, which is in favor of the efficient binding. The opening of mitochondrial permeability transition (MPT) pore is widely accepted as an indicator of mitochondrial dysfunction, which can
Figure 3. (A) Affinity binding curve of Cy5-labeled PPCs and KLAK with isolated mitochondria. n represents the Hill coefficient calculated from Hill plot. (B) Mitochondrial swelling induced by H2O2 treated PPCs and KLAK (10 μM for KLAK) (C) Schematic cartoon of H2O2 treated PPCs and KLAK binding model toward mitochondria.
Figure 4. (A) IC50 of PPCs against HeLa and HCerEpiC cells (N = 3). (B) In vivo fluorescence imaging of tumor bearing mice after injection of PPCs and PBS for 24 h and 48 h. The red circles indicate the tumor sites. (C) Average ex vivo fluorescence signals of major organs and tumor after 96 h post tail-vein injection (N = 3). (D) Tumor volume changes of mice treated by PPCs (N = 6). *p < 0.05, **p < 0.01.
be reflected by mitochondrial swelling assay (Figure 3B). P1 nanofibers cause the distinct swelling of isolated mitochondria, resulting in the decrease of absorbance, which demonstrates fibrous nanostructures dramatically affect the permeabilization of mitochondrial membrane. We speculate that multivalent cooperative interactions also display extraordinary interference on mitochondria in living cell level. The JC-1 (Figure S28 and S29)30 and ROS (Figure S30) assay demonstrate P1 presents excellent mitochondrial disruption ability against HeLa cells, and the IC50 (Figure 4A and S31) of P1 against HeLa cells is ~10 μg mL-1, which is much lower than free KLAK (>100 μg mL-1), P2 (~44 μg mL-1) and P3 (~57 μg mL-1). The obvious detection of cytochrome c in cytoplasm, upregulated Bak, down-regulated Bcl-2 and activated caspase-3/9 further demonstrate transformable P1 induces advanced antitumor ability by triggering mitochondria-dependent apoptosis (Figure S32 and S33). In addition, the ROS levels in normal human cervical epithelial (HCerEpiC) cells treated with PPCs are almost the same, and corresponding cytotoxicity of P1 (IC50 = 38 μg mL-1) is obviously lower than that toward HeLa cells, which can be attributed to the low leveled ROS in normal cells. The cytotoxicity against more varieties of normal cells and tumor cells have also been performed (Figure S34), and P1 can kill cancer cells more efficiently due to their ROS overgeneration (Figure S24). These observations indicate locational nanoparticle-to-nanofiber morphology change only can take place in ROS over-generated cancer cells, exhibiting advanced anticancer ability due to multivalent cooperative interactions. The effect of morphology transformation on tumor accumulation and inhibition capacity is evaluated in vivo. Cy5labeled PPCs can accumulate at tumor site and reach a top at 24 h (Figure 4B and S35), and the average fluorescent intensity of mice treated with P1 is ~2-3 folds higher than P2 and P3 groups in tumor site. Meanwhile, P1 shows the prolonged retention in tumor site within 96 h, which can be ascribed to the AIR effect of locational fibrous structure.31 After 96 h, ex vivo fluorescence imaging of major organs and tumors shows the tumor-specific
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accumulation of P1 nanofibers (Figure S36). The fluorescence intensity of P1 group is about threefold higher than that of P2 and P3 groups (Figure 4C). Moreover, the fibrous structure can be observed by bio-TEM in tumor slices of P1 treated mice, while not for P2, P3 and PBS groups (Figure S37). The in vivo tumor inhibition experiments show P1 presents more efficient antitumor ability than that of P2 and P3. The H&E staining and TUNEL assay further prove the apoptosis of tumor tissues (Figure S38). Therefore, the ROS-triggered locational transformation leads to both improved accumulation in tumor site and enhanced disruption of tumor cells. Furthermore, all the analysis of body weight changes (Figure S39), histopathology (Figure S40) and hematology (Figure S41) exhibit negligible toxicity of PPCs in vivo. In conclusion, endogenous ROS-responsive PPCs are prepared for realizing mitochondria locational assembly. The PPCs can self-assemble into nanoparticles and deliver the cytotoxic peptide KLAK to mitochondria efficiently. Under the highleveled ROS in tumor cells, the hydrophilic PEG is removed off, and then the nanoparticles transform into the fibrous structures with protruding KLAK, exhibiting stronger multivalent cooperative interactions with mitochondria. Finally, the morphology transformation induces advanced antitumor ability in vitro and in vivo. This OLMT strategy offers a novel insight for developing nanomedicines that enhances the drug efficacy. The further research such as selecting another theranostics is undergoing.
ASSOCIATED CONTENT Supporting Information Experimental details, 1H NMR, MALDI-TOF, DLS, CD, CLSM, TEM, as well as the data in vitro and in vivo. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author E-mail:
[email protected],
[email protected] Notes The authors declare no competing financial interests.
ACKNOWLEDGMENT This work was supported by National Natural Science Foundation of China (21674027, 21704020, 31870998 and 51573032) and the National Science Fund for Distinguished Young Scholars (51725302). Dr. Dong-Bing Cheng acknowledges financial support from the China Postdoctoral Science Foundation (2017M620707).
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