Article Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
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Paclitaxel-Promoted Supramolecular Polymerization of Peptide Conjugates Hao Su,† Weijie Zhang,†,‡ Han Wang,† Feihu Wang,† and Honggang Cui*,†,§,∥
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†
Department of Chemical and Biomolecular Engineering, and Institute for NanoBioTechnology, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States ‡ Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Eastern Road, Zhengzhou 450052, Henan, China § Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore, Maryland 21231, United States ∥ Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States S Supporting Information *
ABSTRACT: Spontaneous association above a threshold concentration is a hallmark of supramolecular polymerization, in which monomeric units self-assemble into polymeric aggregates through noncovalent interactions. This selfinitiated supramolecular process differs from the conventional covalent chain-growth polymerization in that the latter often involves the use of a different chemical entity as an initiator to trigger/control the polymerization process. We report here the use of a small molecule hydrophobe, paclitaxel (PTX), as an effective promoter to induce the supramolecular polymerization of a peptide−paclitaxel conjugate, Spheropax (Spax). We found that Spax monomers alone in water self-assemble into spherical micelles of approximately 6.5 nm in diameter but, in the presence of free PTX, undergo a supramolecular polymerization process to form filamentous assemblies of several micrometers in length. Increasing the ratio of promoter to monomer (PTX/Spax) induces Spax’s directional polymerization and expedites its kinetic process. We believe these findings provide important insight into the initiator-controlled supramolecular polymerization process.
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INTRODUCTION Supramolecular polymers,1−3 formed by self-assembly of monomeric units, expand the functional space of covalent polymers, representing an emerging class of polymeric materials with unique and tunable mechanical,4−6 biological,7−13 optical,14−16 and electronic properties.17−19 In contrast to the covalent chain-growth polymerization which often uses different kinds of molecules as catalysts or initiators to trigger and/or control the polymerization process, supramolecular polymerization (SP) at large does not require the addition of a second molecule and occurs in a spontaneous manner under the assembly conditions.20 This kind of polymerization often relies on directional and reversible noncovalent interactions, such as coordination bonds, π−π interactions, or hydrogen bonds, which hold the monomeric units together and guide the polymerization pathways. As a result, the control over an SP process is often achieved through tuning the nature and strength of the involved molecular interactions by varying solution pH,21−23 temperature,24−26 and ionic strength27,28 or by applying enzymes29−31 and/or other external stimuli.32−37 Many attempts have been made over the past decade on the elucidation of the nucleation and growth mechanism of the SP © XXXX American Chemical Society
process with the goal of carrying out the reaction in a more controlled and precise manner.37−50 For example, Manners, Winnik, and co-workers took advantage of the crystallizationdriven self-assembly behavior of amphiphilic block copolymers to create highly monodispersed cylindrical micelles by using uniform crystallite seeds as effective initiators.40,41 Their pioneering work suggested that the unimer-to-crystallite seed (monomer-to-initiator) ratios can be used to tune the length of cylindrical micelles, in a way similar to living ionic polymerization. On the small molecular side, Shimada, Tirrell and coworkers reported the kinetic pathways of forming worm-like micelles by self-assembly of peptide amphiphiles.38 Their work suggested that spherical assemblies are formed as precursors prior to further elongation into supramolecular polymers. To achieve a greater control over the chain growth, the Aida lab demonstrated a chain-growth polymerization of metastable monomers that do not undergo a spontaneous polymerization at ambient temperatures but can be activated by a designed initiator to polymerize in a living polymerization fashion.39 More recently, the Meijer group reported a supramolecular Received: May 2, 2019 Published: June 20, 2019 A
DOI: 10.1021/jacs.9b04730 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
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Self-Assembly and PTX-Promoted Supramolecular Polymerization of Spax. To investigate its self-assembly behavior, Spax was pretreated with hexafluoroisopropanol (HFIP) to disrupt any preformed structures during sample purification.53,54 After complete removal of HFIP, the resultant film was dissolved in Milli-Q water to reach a final concentration of 2 mM. After aging for 2 days at room temperature, cryogenic transmission electron microscopy (cryo-TEM) imaging reveals that Spax self-assembles into monodispersed spherical micelles with a diameter of 6.3 ± 0.7 nm (Figures 1B and S6). The morphology and size were further confirmed using dynamic light scattering (Figure 1C), revealing a hydrodynamic diameter of ∼6.5 nm. Very interestingly, when PTX was added to the 2 mM Spax aqueous solution at a PTX/Spax ratio of 18/100 (section S2.3 in the SI), filamentous assemblies were observed after aging for 12 h. Both cryo-TEM (Figure 1D) and conventional TEM (Figures 1E and S7) confirmed the formation of filamentous polymers of 7.8 ± 1.0 nm in width and up to several micrometers in length. A closer examination reveals a slight variation in width from filament to filament, indicating that their molecular packing resembles more that of peptide-based filamentous assemblies, not that of cylindrical micelles. Circular dichroism (CD) spectroscopy of the Spax aqueous solution alone (Figure S8) shows a broad positive signal at 234 nm and a broad negative peak at 295 nm, attributable to the respective n−π* and π−π* transitions of PTX chromophores.51,52 At the peptide absorption region, there was no indication of α-helical or β-sheet secondary structures. The negative peak at 198 nm suggests that the peptide moiety assumes a random-coil conformation. Adding PTX into the solution led to a notable change in its CD absorption as a result of forming Spax supramolecular polymers. The negative peak at 295 nm, along with the strong positive peak at 234 nm with a shoulder at 212 nm, implies that the PTX molecules are packed in a more ordered fashion within the supramolecular polymers. We speculate the intermolecular hydrogen bonding among the peptide segments is accountable for the observed one-dimensionality; however, the typical absorption for β-sheet assemblies, a strong negative at ∼216 nm, was not observed, most likely due to its overlapping with the PTX absorption in this range. These results suggest that adding the small molecule PTX dramatically alters the assembly landscape of Spax by promoting its directional supramolecular growth. Polymerization at Various PTX/Spax Ratios. We further discovered that the formation of the Spax supramolecular polymers is highly dependent upon the promoter/ monomer ratio. We prepared a series of Spax aqueous solution with a respective PTX/Spax ratio of 6/100, 11/100, 18/100, and 29/100 and aged each solution for 12 h. At the ratio of 6/ 100, TEM imaging revealed predominant spherical assemblies (Figure 2A). A mixture of spheres and short filaments with measured lengths of 440 ± 177 nm (Figure S9) was observed when the ratio was increased to 11/100 (Figure 2B). Long filaments started to appear at the ratio of 18/100 or higher, but their diameters varied slightly from 7.8 ± 1.0 nm for 18/100 (Figure 1D and E) to 10.2 ± 1.0 nm for 29/100 (Figure 2C). An increase in width suggests that the added PTX induces both directional and lateral supramolecular growth of the conjugates. It is also possible that the encapsulation of PTX itself could increase the physical volume and thus expand the width.54 To investigate the molecular packing within the assemblies, we performed CD spectroscopic studies of these
copolymerization strategy to consolidate the stability of supramolecular polymers based on benzene-1,3,5-tricarboxamide (BTA).42 They designed and synthesized two monomers of varying hydrophilic moiety: one with dendronized (dBTA) ethylene glycol; the other with linear (nBTA) ethylene glycol. The former is not able to self-polymerize in water, only forming spherical aggregates, whereas the latter associates spontaneously into filamentous assemblies. Copolymerization of the two BTA monomers resulted in supramolecular polymers with enhanced stability. These studies reveal the importance of controlling both the nucleation and growth kinetics in SP, as well as the effective use of a second type of molecules to tune the process. In this context, we report our discovery that the SP of a peptide conjugate can be specifically activated by a hydrophobic small molecule, paclitaxel (PTX), with tunable polymerization kinetics mimicking the conventional chain-growth polymerization (Scheme 1). Scheme 1. Illustration of Conventional Covalent ChainGrowth Polymerization of Monomers by an Initiator (A), Supramolecular Polymerization through Spontaneous Association of Monomers (B), and Promoted Supramolecular Polymerization Triggered by a Promoter (C)
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RESULTS AND DISCUSSION Molecular Design. Figure 1A shows the molecular design of the studied self-assembling monomer, Spheropax (Spax), consisting of the hydrophobic PTX and a short peptide segment that is capped with four oligo ethylene glycol (OEG), GNNQQKOEGKOEGKOEGKOEG. Details of the Spax synthesis can be found in the Supporting Information (SI). In brief, the peptide segment of (Cys(Ac)-GNNQQKKKK) was synthesized manually using standard Fmoc solid-phase synthesis protocols, followed by the OEG grafting onto the lysine side chains (Figure S1). The synthesis of the Spax monomer was achieved through disulfide formation by reaction of PTX-bussPyr with the peptide precursor in DMSO, similar to a previously reported method.51,52 The final product was purified using reversed-phase HPLC (Figure S1), and its purity and molecular masses were confirmed using analytical HPLC and mass spectrometry, respectively (Figures S2 and S3). B
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Figure 1. Molecular assembly and PTX-promoted supramolecular polymerization of Spax. (A) Chemical structure and cartoon illustration of Spheropax (Spax) that spontaneously aggregates into spheres in water and is able to form filaments by hydrophobic PTX-promoted supramolecular polymerization in aqueous solution. Representative cryo-TEM (B) and DLS data (C) of spheres formed by Spax in water after 2 days at a concentration of 2 mM. The spheres have diameters of 6.3 ± 0.7 nm measured from cryo-TEM images and hydrodynamic diameters of 6.5 nm with PDI = 0.03 measured from DLS. Cryo-TEM (D) and conventional negative-staining TEM (E) images of filaments formed by PTXpromoted supramolecular polymerization of Spax after 12 h in water at a PTX/Spax ratio of 18/100 and Spax concentration of 2 mM. The filaments are 7.8 ± 1.0 nm in width and up to several micrometers in length measured from conventional TEM images.
solution samples. We found that, with the increase of the PTX/ Spax ratio, the chromophore absorption of PTX gradually intensified at both n−π* and π−π* transition regions, along with the emergence of two respective shoulder peaks around 212 and 251 nm (Figure 2D). These observations suggest that the PTX/Spax ratio is critical for the formation of Spax supramolecular polymers, and the increased amount of free PTX enhanced the chiral alignment among PTX units, thus leading to a higher degree of internal order. Kinetic Study of PTX-Promoted Supramolecular Polymerization of Spax. Given that the kinetical pathways can shed light on the self-assembly mechanisms,38,55 we performed time-dependent studies of Spax supramolecular polymerization at a PTX/Spax ratio of 20/100. After aging the solution for 1, 4, 8, 12, and 24 h, we collected a series of TEM images at each incubation time (Figure 3A−E). Figure 3A shows the formation of dominant spherical particles, with a few short filamentous nanostructures spotted on the TEM grids at 1 h. With time, more and longer filaments started to appear and became dominant after 12 h. CD spectra (Figure 3F) were also recorded at different time points, showing a continuous increase in PTX absorption that levels out after 12 h. A corresponding DLS study (Figure S10) also reveals a continuous increase in size with incubation time, and no small aggregates around 10 nm were observed after 12 h incubation. To further confirm this, we also studied the kinetic pathways of Spax solutions at three much lower PTX/Spax ratios: 3/100, 6/100, and 8/100 (Figure S11). At the ratio of 3/100, spherical particles dominated the assembled morphology even up to a 7-day incubation time, and only after 5 days did a select few short filaments (marked with white arrows) pop up from our TEM imaging results (Figure S11A−C). Spax
Figure 2. Supramolecular polymerization of Spax after 12 h incubation at various PTX/Spax ratios. TEM images of assemblies at PTX/Spax ratios of 6/100 (A), 11/100 (B), and 29/100 (C) showed spheres of various sizes, a mixture of spheres and filaments, and filaments with 10.2 ± 1.0 nm in width and several micrometers in length, respectively. TEM image at a PTX/Spax ratio of 18/100 was shown in Figure 1D and E. CD spectra (D) of the studied solutions at various PTX/Spax ratios. The chromophore absorption of PTX gradually intensifies as the PTX/Spax ratio is increased.
C
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assemblies. As the PTX PTX/Spax ratio is increased to 8/100, filamentous structures were observed at earlier time points, appearing as a dominant morphology at 36 h (Figure S11H and I). These studies suggest that increasing the ratio of promoter to monomer expedites the kinetic processes of the Spax polymerization, enabling the possibility for controlled supramolecular polymerization by varying the amount of PTX added. Proposed Mechanism of PTX-Promoted Self-Assembly of Spax. These results collectively led us to propose an assembly mechanism (Figure 3G) that is linked to the dual molecular nature of Spax as both a surfactant and peptide conjugate. In aqueous solution, the Spax monomer alone behaves like conventional low-molecular-weight surfactants and self-assemble into spherical core−shell micelles. Indeed, the diameter of the observed micelles is reasonably close to twice the Spax length with a random coil conformation. In the presence of PTX, the associative interactions between free PTX and the conjugated PTX facilitate and further promote the formation of hydrogen bonding network among the peptide segment thus leading to its directional supramolecular growth, reminiscent of that of peptide amphiphiles. According to a molecular simulation study by Velichko, Stupp, and Olvera,56 the assembly of a classic β-sheetcontaining peptide amphiphile in aqueous solution can undergo two distinct pathways toward the formation of supramolecular polymers, depending on the strength of hydrogen bonding relative to the interactions among hydrophobic units. In the regime where hydrophobic interactions dominate, micellar aggregates are first formed, followed by the formation of hydrogen bonding in the corona that eventually results in supramolecular polymeric growth. Experimentally, Shimada, Tirrell and co-workers observed the formation of spherical micelles as a precursor morphology prior to their elongation into long filamentous structures.38 In our case, the hydrogen bonding capacity of the Spax’s peptide segment was somehow completely inhibited in water. Even at a concentration of 8 mM and after aging for several days, there is no indication of forming cylindrical micelles or filamentous nanostructures. It is plausible that the hydration of the four
Figure 3. Kinetic pathways and proposed mechanism of PTXpromoted supramolecular polymerization of Spax. Time-dependent TEM images of a Spax aqueous solution at a PTX/Spax ratio of 20/ 100 after aging for 1 h (A), 4 h (B), 8 h (C), 12 h (D), and 24 h (E) showed the morphological transition from spherical micelles to supramolecular filaments as the incubation time is increased. (F) Corresponding CD spectra of the solution at different time points. (G) Schematic illustration of the proposed mechanism. Upon addition of water, PTX and Spax quickly aggregate into spherical assemblies with free PTX encapsulated in the core, which gradually undergo morphological transition, molecular rearrangement, and directional growth into supramolecular polymers of several micrometers in length.
solutions of 6/100 did not show any noticeable filamentous growth until 36 h (Figure S11D), at which supramolecular filaments can be sparsely observed on several occasions (inserted image in Figure S11D, and marked with black arrow). Only until after 5 days can long filaments be frequently observed (Figure S11E and S11F), coexisting with spherical
Figure 4. Intermediates (“brush” morphology) formed during the PTX-promoted supramolecular polymerization of Spax. Cryo-TEM (A and B) and conventional TEM images (C−E) of “brush” morphologies observed from a sample solution at a PTX/Spax ratio of 18/100 at 12 h. Image F was from a sample solution at a PTX/Spax ratio of 8/100 at 72 h. Image G was from a sample solution at a PTX/Spax ratio of 29/100 at 12 h. D
DOI: 10.1021/jacs.9b04730 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
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Journal of the American Chemical Society OEG segments poses a strong steric effect that effectively suppresses hydrogen bonding among the peptide moieties. The added free PTX is expected to interact with the conjugated PTX in the micellar core to alleviate the steric effect and thus activate the conjugate’s ability for specific directional interactions. Given that peptide assembly often follows a nucleation and growth kinetic process, we speculate that the added PTX−PTX interactions led to molecular rearrangement of the PTX−peptide conjugates so as to form some precursor structures that serve as nucleation sites for further supramolecular propagation. These nucleation centers lower the energy barriers for morphological elongation. In this sense, the free PTX does act essentially as initiators to facilitate the formation of the observed Spax supramolecular polymers. The impact of molecular ratios of PTX/Spax on the growth kinetics implies that the added PTX not only triggers the polymerization by rearranging the molecular packing within Spax spherical assemblies to form nucleation sites but also facilitates the consequent propagation by participating in the supramolecular growth process (Figure 3G). The PTX’s role in propagation bears some resemblances to the copolymerization work reported by the Meijer lab.42 However, unlike their system in which a true copolymerization was observed, the two monomers involved were both self-assembling units. The free PTX in our system has an extremely low water solubility (solubility in pure water is ∼0.35 μM)57,58 and is unable to self-polymerize to form any well-defined structures in aqueous solution. Its role, in our opinion, is to alter the arrangement of molecules with Spax spherical assemblies to create nucleation sites and to induce their supramolecular growth. In this sense, the added PTX acts as more of a promoter than a copolymerizing agent, or an initiator. The proposed mechanism can be further supported by the capture of some “brush” intermediate morphologies formed during the PTX-promoted polymerization process. Both cryoTEM (Figure 4A and B) and conventional TEM (Figure 4C − E) images clearly revealed multiple filaments sprouting from a nucleation hub. It should be noted these “brushes” can be observed for nearly all the samples studied (Figures 4F, 4G, and S12), and they appeared much more frequently for those with a higher PTX/Spax ratio. A common feature for all the observed “brush” morphology is that filaments are developed from two sides of a center hub. The uniform contrast across the central hub under TEM imaging indicates a planar structure, which is similar to a previously reported “broom’ morphology by the Stupp lab.59 Presumably, the long axial of the sprouting filaments is a result of directional hydrogen bonding, while the lateral growth could also be linked to the enhanced PTX−PTX interactions that similarly lower the energy barriers for molecular association perpendicular to the hydrogen bonding directions. These intermediates provide direct mechanistic insight into the PTX-promoted SP process. To better understand the role that the hydrophobic PTX played as an effective promoter in the SP process, we attempted to use another hydrophobic molecule camptothecin (CPT) to activate the polymerization of Spax (Figure 5A). In sharp contrast to the bulky PTX, CPT has a planar structure of much smaller size. In this experiment, HFIP-pretreated CPT and Spax were first mixed at a 1/1 molar ratio, and after complete removal of HFIP, the mixtures were redissolved in aqueous solution to reach a final Spax concentration of 2 mM (section S2.3 in the SI). We found that only 2% of CPT can be successfully incorporated into the Spax assemblies after
Figure 5. Self-assembly of Spax after the addition of CPT. (A) Chemical structure of CPT. (B) Conventional TEM image of a Spax solution at a CPT/Spax ratio of 2/100 after aging for 48 h. Only small spherical aggregates were observed. The initial feeding molar ratio of CPT/Spax was 1/1; however, only 2% of CPT was successfully incorporated into the Spax assemblies. (C) The spherical assemblies in CPT/Spax solution have a hydrodynamic diameter of 6.7 nm with PDI = 0.04, measured from DLS. (D) CD spectra of Spax (black) and CPT/Spax (red).
removal of the unencapsulated CPT. Conventional TEM imaging reveals that the CPT/Spax mixture assembles into small spherical aggregates, and no filamentous nanostructures were observed after aging for 48 h (Figure 5B). The spherical assemblies were further confirmed by DLS, showing a hydrodynamic diameter of 6.7 nm (Figure 5C) similar to that of the Spax assemblies. CD spectroscopy of CPT/Spax solution also reveals an almost identical absorption to that of Spax alone (Figure 5D). All of these results suggest that the hydrophobic CPT, unlike PTX, is unable to promote the supramolecular polymerization of Spax. In this case, the added CPT may not be sufficient to rearrange molecular packing in the hydrophobic domain due to (1) the structural dissimilarity between CPT and PTX and (2) the inadequate amount of CPT incorporated. This led us to conclude that the enhanced PTX−PTX interaction is essential to promote the formation of supramolecular filaments. To further confirm our hypothesis that the PTX-promoted SP is a result of enhanced molecular interactions exerted by the added free PTX, we synthesized another PTX−peptide conjugate Fpax, GNNQQKOEGKOEGKOEG, with a reduced number of OEG hydrophilic segment (3 OEGylated lysine side chains versus 4 in Spax) (Figures 6A, S1, S3, and S5). The Fpax possesses a higher hydrophilic−lipophilic balance (HLB) value for more potent assembly in water and also reduces the steric hindrance for hydrogen bonding among the peptide segment. Indeed, upon dissolution in water, the Fpax monomers were observed to form filamentous nanostructures at a concentration of 2 mM after aging for 12 h (Figure 6A). Representative cryo-TEM (Figure 6B) and conventional TEM (Figure 6C) imaging reveals that Fpax self-assembles into supramolecular nanobelts of 11.1 ± 1.3 nm in width and up to E
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Figure 6. Molecular assembly of Fpax. (A) Chemical structure and illustration of the designed Filopax (Fpax) that self-assembles into nanobelts in aqueous solution. Representative cryo-TEM (B) and conventional negative-staining TEM (C) images of supramolecular nanobelts formed by Filopax self-assembly in water at the concentration of 2 mM after aging for 12 h. The nanobelts are 11.1 ± 1.3 nm in width and up to several micrometers in length, measured from conventional TEM images. (D) CD spectra of Fpax (black curve) and Spax (red curve). Compared with Spax, the Fpax showed a negative hydrogen bonding absorption at 209 nm and slightly increased PTX chromophore interactions around 234 nm.
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several micrometers in length. CD spectrum of Fpax demonstrates a negative peak at 209 nm attributing to the absorption related to hydrogen bonding, and an intensified PTX absorption around 234 nm (Figure 6D). These observations suggest that supramolecular polymerization of the PTX−peptide conjugate can occur spontaneously when designed appropriately. In the case of the Spax design in which supramolecular polymerization cannot proceed in a spontaneous manner, adding a sufficient amount of free PTX promotes associative interactions to overcome the steric hindrance and hydration forces for directional supramolecular growth.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.9b04730. Details of molecular synthesis and characterization, additional TEM and cryo-TEM images of the PTXpromoted polymerization and their kinetic pathways, CD measurement, histogram of filament length, and dynamic light scattering studies (PDF)
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AUTHOR INFORMATION
Corresponding Author
*
[email protected] CONCLUSION
ORCID
Feihu Wang: 0000-0002-0358-967X Honggang Cui: 0000-0002-4684-2655
In this article, we demonstrated that a poorly water-soluble small molecule can be used to trigger supramolecular polymerization of a peptide-based monomeric unit that does not self-polymerize. The added free PTX interacts with the conjugate PTX moieties, creating nucleation clusters that lower the energy barriers for their further aggregation and growth into ordered filamentous structures. Importantly, we found that the PTX/Spax ratio plays a key role in determining the polymerization kinetics, and thus can be used to tune/control the SP process. While we have not yet demonstrated all the essential features of controlled living supramolecular polymerization in terms of the filament length and the length polydispersity, our results lay out the foundation for using a second small molecule to specifically turn on the supramolecular polymerization of a self-assembling unit. The work herein should motivate more research into the development of SP promoters, initiators, or even inhibitors, to selectively promote, activate, or terminate the polymerization process, which could eventually lead to well-controlled living supramolecular polymerization matching up to the current development of chain-growth living polymerization.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The work reported here is supported by the National Science Foundation (DMR-1506937). We thank the Johns Hopkins University (JHU) Integrated Imaging Center (IIC) for the use of the TEM facility, and the JHU Department of Chemistry Mass Spectrometry facility.
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DOI: 10.1021/jacs.9b04730 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
