Marcromolecular Architecture and Encapsulation of the Anticancer Drug Everolimus Control the Self-Assembly of Amphiphilic Polypeptide-Containing Hybrids

Karatzas, Anastasios; Haataja, Johannes S.; Skoulas, Dimitrios; Bilalis, Panayiotis; Varlas, Spyridon; Apostolidi, Panagiota; Sofianopoulou, Sosanna; Stratikos, Efstratios; Houbenov, Nikolay; Ikkala, Olli; Iatrou, Hermis

doi:10.1021/acs.biomac.9b01331

Cited by 9 publications

(5 citation statements)

References 85 publications

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“…Interestingly, hybrids based on the linear PEG showed almost no partially cleaved intermediates, indicating that the rate limiting step of its degradation and disassembly is the escape from the micelles and once encountered outside of the micelles by the enzyme, it can get fully cleaved. Higher stability of the V-shaped architecture toward complete enzymatic degradation was also reported recently by Iatrou and co-workers, which reported triblocks containing linear or V-shaped poly(ethylene oxide) (PEO) as the terminal block, poly( l -histidine- co -γ-benzyl- l -glutamate) as the hydrophobic block, and poly( l -lysine hydrochloride) as the second terminal hydrophilic block. The reported V-shape containing PEG triblocks self-assembled into vesicles and micelles that showed higher stability toward enzymatic degradation in comparison with the linear PEG containing analogues.…”

Section: Resultssupporting

confidence: 78%

Architectural Change of the Shell-Forming Block from Linear to V-Shaped Accelerates Micellar Disassembly, but Slows the Complete Enzymatic Degradation of the Amphiphiles

et al. 2020

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Tuning the enzymatic degradation and disassembly rates of polymeric amphiphiles and their assemblies is crucial for designing enzyme-responsive nanocarriers for controlled drug delivery applications. The common methods to control the enzymatic degradation of amphiphilic polymers are to tune the molecular weights and ratios of the hydrophilic and hydrophobic blocks. In addition to these approaches, the architecture of the hydrophilic block can also serve as a tool to tune enzymatic degradation and disassembly. To gain a deeper understanding of the effect of the molecular architecture of the hydrophilic block, we prepared two types of well-defined PEG-dendron amphiphiles bearing linear or V-shaped PEG chains as the hydrophilic blocks. The high molecular precision of these amphiphiles, which emerges from the utilization of dendrons as the hydrophobic blocks, allowed us to study the self-assembly and enzymatic degradation and disassembly of the two types of amphiphiles with high resolution. Interestingly, the micelles of the V-shaped amphiphiles were significantly smaller and disassembled faster than those of the amphiphiles based on linear PEG. However, the complete enzymatic cleavage of the hydrophobic end groups was significantly slower for the V-shaped amphiphiles. Our results show that the V-shaped architecture can stabilize the unimer state and, hence, plays a double role in the enzymatic degradation and the induced disassembly and how it can be utilized to control the release of encapsulated or bound molecular cargo.

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Section: Resultssupporting

confidence: 78%

Architectural Change of the Shell-Forming Block from Linear to V-Shaped Accelerates Micellar Disassembly, but Slows the Complete Enzymatic Degradation of the Amphiphiles

et al. 2020

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“…To determine the molar mass ( M n and M w ) and the dispersity index ( Đ , or else PDI), measurements by SEC were performed utilizing Chloroform at 25 °C at a flow rate of 1 mL/min. The SEC system was composed of a Waters 600 high-performance liquid chromatographic pump, Waters Ultrastyragel columns HR-1, HR-2, HR-4E, HR-4, and HR-5, and a Shimadzu RID-10A refractive index detector.…”

Section: Methodsmentioning

confidence: 99%

Synthesis, Crystallization, Structure Memory Effects, and Molecular Dynamics of Biobased and Renewable Poly(n-alkylene succinate)s with n from 2 to 10

et al. 2021

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In this article, we synthesize five poly(n-alkylene succinate)s, PnASs, with n = 2, 4, 6, 8, and 10 via multi-step polycondensation methods. Next, we comparatively investigate these renewable and biobased polyesters from the points of view of structure, crystallinity, and molecular mobility, employing 1 H nuclear magnetic resonance spectroscopy, size-exclusion chromatography, viscometry, X-ray diffraction, differential scanning calorimetry (DSC, conventional and temperature modulation modes), polarized optical microscopy (POM), and broadband dielectric relaxation spectroscopy (BDS). Next to the successful synthesis of the materials, we evaluate the characteristics of crystallization (temperature and fraction); moreover, we explore for the first time, on the same type of succinic polyesters, the impact of n on the structure memory related to crystal nucleation as well as the changes in the semicrystalline morphology. We demonstrate that the structure/crystal memory is stronger for the lower n (shorter alkylene succinate monomers) because of more chain−chain associations, the result being independent from the overall length of the polymer chain (molar mass, M n 13−80 kg/mass). The crystalline fraction (CF ∼ 12− 34%) increases with n, also independently from M n ; however, the chain length affects directly the nucleation rate as T c increases with M n . The direct effects of n, in the inter-/intrachain interactions, as well as the indirect ones, on the CF and distribution of crystallites were found to be responsible for the alternations in the static glass transition temperature in DSC (lowering of T g with n) and the dynamic glass transition (α, α c relaxations in BDS). For the sum of these PnASs, the molecular dynamics mapping is shown here, also for the first time. With increasing n, segmental dynamics accelerates, whereas, interestingly, the cooperativity drops (elimination for n = 10). Comparing these results with the recorded alternations in the semicrystalline morphology (POM), we conclude spatial confinement to be imposed on the mobile amorphous polymer by the tightly distributed crystallites when n increases. Overall, these data provide proofs for the potential for tuning of the final polymer properties connected with crystallization (mechanical performance and permeability), envisaging future biomedical, packaging, and other application for these PnASs.

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“…The transformation of the secondary structure of the block-graft copolypeptide is due to PHIS, which has pKa = 6.5. In a previous work, we have found that PHIS adopts a β-turn conformation at pH higher than 7.4, while it transforms to random coil by lowering the pH and becoming protonated [26][27][28][29][30]. Figure 15 provides the Circular Dichroism data for the PLL 78 -b-(PLL 10 -g-PHIS 15 ) at pH values 5.0, 6.5, and 7.4.…”

Section: Study Of the Secondary Structure Of Pll 78 -B-(pll 10 -G-phimentioning

confidence: 95%

Synthesis and Characterization of the Novel Nε-9-Fluorenylmethoxycarbonyl-l-Lysine N-Carboxy Anhydride. Synthesis of Well-Defined Linear and Branched Polypeptides

et al. 2020

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The synthesis of well-defined polypeptides exhibiting complex macromolecular architectures requires the use of monomers that can be orthogonally deprotected, containing primary amines that will be used as the initiator for the Ring Opening Polymerization (ROP) of N-carboxy anhydrides. The synthesis and characterization of the novel monomer Nε-9-Fluorenylmethoxycarbonyl-l-Lysine N-carboxy anhydride (Nε-Fmoc-l-Lysine NCA), as well as the novel linear Poly(Nε-Fmoc-l-Lys)n homopolypeptide and Poly(l-Lysine)78–block–[Poly(l-Lysine)10–graft–Poly(l-Histidine)15] block-graft copolypeptide, are presented. The synthesis of the graft copolypeptide was conducted via ROP of the Nε-Boc-l-Lysine NCA while using n-hexylamine as the initiator, followed by the polymerization of Nε-Fmoc-l-Lysine NCA. The last block was selectively deprotected under basic conditions, and the resulting ε-amines were used as the initiating species for the ROP of Nim-Trityl-l-Histidine NCA. Finally, the Boc- and Trt- groups were deprotected by TFA. High Vacuum Techniques were applied to achieve the conditions that are required for the synthesis of well-defined polypeptides. The molecular characterization indicated that the polypeptides exhibited high degree of molecular and compositional homogeneity. Finally, Dynamic Light Scattering, ζ-potential, and Circular Dichroism measurements were used in order to investigate the ability of the polypeptide to self-assemble in different conditions. This monomer opens avenues for the synthesis of polypeptides with complex macromolecular architectures that can define the aggregation behavior, and, therefore, can lead to the synthesis of “smart” stimuli-responsive nanocarriers for controlled drug delivery applications.

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Marcromolecular Architecture and Encapsulation of the Anticancer Drug Everolimus Control the Self-Assembly of Amphiphilic Polypeptide-Containing Hybrids

Cited by 9 publications

References 85 publications

Architectural Change of the Shell-Forming Block from Linear to V-Shaped Accelerates Micellar Disassembly, but Slows the Complete Enzymatic Degradation of the Amphiphiles

Architectural Change of the Shell-Forming Block from Linear to V-Shaped Accelerates Micellar Disassembly, but Slows the Complete Enzymatic Degradation of the Amphiphiles

Synthesis, Crystallization, Structure Memory Effects, and Molecular Dynamics of Biobased and Renewable Poly(n-alkylene succinate)s with n from 2 to 10

Synthesis and Characterization of the Novel Nε-9-Fluorenylmethoxycarbonyl-l-Lysine N-Carboxy Anhydride. Synthesis of Well-Defined Linear and Branched Polypeptides

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