Modular Synthetic Approach for Adjusting the Disassembly Rates of Enzyme-Responsive Polymeric Micelles

Harnoy, Assaf J.; Buzhor, Marina; Tirosh, Einat; Shaharabani, Rona; Beck, Roy; Amir, Roey J.

doi:10.1021/acs.biomac.6b01906

Cited by 31 publications

(47 citation statements)

References 47 publications

(86 reference statements)

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“…The obtained values indeed showed the expected trend, which correlates well with previous reports. 45 After confirming the self-assembly of nanostructures in aqueous environment, we used dynamic light scattering (DLS) to measure the sizes of the formed structures. We determined the diameters of the assembled structures to be in the range of 14-31 nm (table 1), which indicates that the amphiphiles self-assembled into nano-sized micelles.…”

Section: Self-assembly Into Micellar Nanoreactorsmentioning

confidence: 99%

Tuning Reactivity of Micellar Nanoreactors by Precise Adjustments of the Amphiphiles and Substrates Hydrophobicity

Tevet¹,

Wagle²,

Slor³

et al. 2021

Preprint

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Polymeric assemblies, such as micelles, are gaining increasing attention due to their ability to serve as nanoreactors for the execution of organic reactions in aqueous media. The ability to conduct transformations, which have been limited to organic media, in water is essential for the further development of the important fields of greencatalysis and bioorthogonal chemistry, among other fields. In light of the recent progress in the expanding the scopes of reactions that can be conducted using nanoreactors, we aimed to gain deeper understanding of the roles of the hydrophobicity of both the core of micellar nanoreactors and the substrates on the reaction rates in water. Towards this goal we designed a set of metal-loaded micelles, composed of PEG-dendron amphiphiles and studied their ability to serve as nanoreactors for a palladium mediated depropargylation reaction of four substrates with different LogP values. Using dendrons as the hydrophobic block, allowed us to fine tune the lipophilicity of the dendritic end-groups and study how precise structural changes in the hydrophobicity of the amphiphiles affect the reaction rates. The kinetic data revealed linear relations between the rate constants and the hydrophobicity of the amphiphiles (estimated by the dendron’scLogP), while exponential dependence was obtained for the lipophilicity of the substrates (estimated by their LogP values). Our results demonstrate the vital contributions of the hydrophobicity of both the substrates and amphiphiles on the lipo-selectivity of nanoreactors, illustrating the potential of tuning hydrophobicity as a tool for optimizingthe reactivity and selectivity of nanoreactors.

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Section: Self-assembly Into Micellar Nanoreactorsmentioning

confidence: 99%

Tuning Reactivity of Micellar Nanoreactors by Precise Adjustments of the Amphiphiles and Substrates Hydrophobicity

Tevet¹,

Wagle²,

Slor³

et al. 2021

Preprint

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“…The product was obtained as an off-white solid in 90% yield (2.1 g). 1 H-NMR (CDCl 3 ): δ 7.27 (d, J = 2.4 Hz, 2H, arom H), 6.75 (t, J = 2.4 Hz, 1H, arom H), 6.01-6.10 (m, 2H, vinylic H), 5.43 (dd, J = 17.3 Hz, 1.6 Hz, 2H, trans vinylic H), 5.31 (dd, J = 10.5 Hz, 1.5 Hz, 2H, cis vinylic H), 4.57 (dt, J = 5.3 Hz, 1.6 Hz, 4H, allylic H); 13 4-nitrophenyl 3,5-bis(allyloxy)benzoate (compound 1): 3,5-bis(allyloxy)benzoic acid (2.0 g, 8.5 mmol) was dissolved in THF (40 mL). 4-nitrophenol (1.3 g, 9.35 mmol, 1.1 eq.…”

Section: Synthesismentioning

confidence: 99%

“…3,5-bis(propargyloxy)benzoic acid and 4-nitrophenyl-3,5-bis(propargyloxy)benzoate were synthesized as described for the preparation of 3,5-bis(allyloxy)benzoic acid and 4nitrophenyl-3,5-bis(propargyloxy)benzoate, respectively, and the spectroscopic data correlated to the data that has been already published. 1 Figure S5: 1…”

Section: Synthesis Of Bis-propargyloxy Branching Unitmentioning

confidence: 99%

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Mixing End Groups in Thiol-Ene/Yne Reactions as a Simple Approach toward Multienzyme-Responsive Polymeric Amphiphiles

Harnoy

Papo

Slor

et al. 2018

Synlett

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Taking advantage of the high fidelity of thiol-ene and thiol-yne chemistries, we used mixtures of thiols to prepare degradable PEG-dendron amphiphiles functionalized with two different types of enzymatically cleavable end groups. By tuning the feed ratios of the two thiols, we achieved mixtures of hybrids with statistically different ratios of end groups. Studies of the disassembly of statistically mixed hybrids showed that these amphiphiles have higher degrees of response when incubated with each of the activating enzymes, whereas a greater degree of selectivity was observed for a control mixture of two distinct amphiphiles, which required the presence of both types of enzyme to undergo complete disassembly. The potential to introduce different end groups by using a mixture of thiols in an efficient single thiol-ene or thiol-yne step opens the way for simple modification of various ene- or yne-containing polymers and tailoring of their structural and functional properties.

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“…In addition, enzyme responsive polymers have shown high potential for long-term cycling and targeted therapy and diagnosis of disease in vivo [10]. However, although some enzyme responsive linear-linear block copolymers have been investigated, until recently, only a few studies related to enzyme responsive linear-dendritic block copolymers (LDBCs) have been reported [11,12].…”

Section: Introductionmentioning

confidence: 99%

Self-Assembly and Enzyme Responsiveness of Amphiphilic Linear-Dendritic Block Copolymers Based on Poly(N-vinylpyrrolidone) and Dendritic Phenylalanyl-lysine Dipeptides

et al. 2019

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In this study, we present the synthesis, self-assembly, and enzyme responsive nature of a unique class of well-defined amphiphilic linear-dendritic block copolymers (PNVP-b-dendr(Phe-Lys)n, n = 1–3) based on linear poly(N-vinylpyrrolidone) (PNVP) and dendritic phenylalanyl-lysine (Phe-Lys) dipeptides. The copolymers were prepared via a combination ofreversible addition-fragmentation chain transfer (RAFT)/xanthates (MADIX) polymerization of N-vinylpyrrolidone and stepwise peptide chemistry. The results of fluorescence spectroscopy, 1H NMR analyses, transmission electron microscopy (TEM), and particle size analysis demonstrated that the copolymers self-assemble in aqueous solution into micellar nanocontainers that can disassemble and release encapsulated anticancer drug doxorubicin or hydrophobic dye Nile red by trigger of a serine protease trypsin under physiological conditions. The disassembly of the formed micelles and release rates of the drug or dye can be adjusted by changing the generation of dendrons in PNVP-b-dendr(Phe-Lys)n. Furthermore, the cytocompatibility of the copolymers have been confirmed using human lung epithelial cells (BEAS-2B) and human liver cancer cells (SMMC-7721). Due to the fact of their enzyme responsive properties and good biocompatibility, the copolymers may have potential applicability in smart controlled release systems capable of site-specific response.

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Modular Synthetic Approach for Adjusting the Disassembly Rates of Enzyme-Responsive Polymeric Micelles

Cited by 31 publications

References 47 publications

Tuning Reactivity of Micellar Nanoreactors by Precise Adjustments of the Amphiphiles and Substrates Hydrophobicity

Tuning Reactivity of Micellar Nanoreactors by Precise Adjustments of the Amphiphiles and Substrates Hydrophobicity

Mixing End Groups in Thiol-Ene/Yne Reactions as a Simple Approach toward Multienzyme-Responsive Polymeric Amphiphiles

Self-Assembly and Enzyme Responsiveness of Amphiphilic Linear-Dendritic Block Copolymers Based on Poly(N-vinylpyrrolidone) and Dendritic Phenylalanyl-lysine Dipeptides

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