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

Wei, Junwu; Lin, Feng; You, Dan; Qian, Yangyang; Wang, Yujia; Yun-mei, BI

doi:10.3390/polym11101625

Cited by 14 publications

(12 citation statements)

References 48 publications

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“…Amph-PVP-based nanocarriers were proposed for the delivery of non-steroidal anti-inflammatory drugs [ 39 , 40 ] and for drug delivery into the cell nucleus [ 41 ]. Moreover, amphiphilic linear-dendritic block copolymers based on the linear PVP and dendritic phenylalanyl-lysine dipeptide were reported for the enzyme-responsive release of doxorubicin [ 42 ]. However, we did not find any reports, where Amph-PVP-based nanocarriers were proposed for targeted hydrophilic therapeutic macromolecules, namely targeted proteins.…”

Section: Discussionmentioning

confidence: 99%

Amphiphilic Poly(N-vinylpyrrolidone) Nanoparticles Conjugated with DR5-Specific Antitumor Cytokine DR5-B for Targeted Delivery to Cancer Cells

et al. 2021

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Nanoparticles based on the biocompatible amphiphilic poly(N-vinylpyrrolidone) (Amph-PVP) derivatives are promising for drug delivery. Amph-PVPs self-aggregate in aqueous solutions with the formation of micellar nanoscaled structures. Amph-PVP nanoparticles are able to immobilize therapeutic molecules under mild conditions. As is well known, many efforts have been made to exploit the DR5-dependent apoptosis induction for cancer treatment. The aim of the study was to fabricate Amph-PVP-based nanoparticles covalently conjugated with antitumor DR5-specific TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand) variant DR5-B and to evaluate their in vitro cytotoxicity in 3D tumor spheroids. The Amph-PVP nanoparticles were obtained from a 1:1 mixture of unmodified and maleimide-modified polymeric chains, while DR5-B protein was modified by cysteine residue at the N-end for covalent conjugation with Amph-PVP. The nanoparticles were found to enhance cytotoxicity effects compared to those of free DR5-B in both 2D (monolayer culture) and 3D (tumor spheroids) in vitro models. The cytotoxicity of the nanoparticles was investigated in human cell lines, namely breast adenocarcinoma MCF-7 and colorectal carcinomas HCT116 and HT29. Notably, DR5-B conjugation with Amph-PVP nanoparticles sensitized resistant multicellular tumor spheroids from MCF-7 and HT29 cells. Taking into account the nanoparticles loading ability with a wide range of low-molecular-weight antitumor chemotherapeutics into hydrophobic core and feasibility of conjugation with hydrophilic therapeutic molecules by click chemistry, we suggest further development to obtain a versatile system for targeted drug delivery into tumor cells.

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Section: Discussionmentioning

confidence: 99%

Amphiphilic Poly(N-vinylpyrrolidone) Nanoparticles Conjugated with DR5-Specific Antitumor Cytokine DR5-B for Targeted Delivery to Cancer Cells

et al. 2021

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“…25 In this study, a similar protocol was employed for the one-step synthesis of PNVCL with a BocNH end-group (PNVCL n -NHBoc), whereas the reported earlier synthesis of BocNH-terminated poly(N-vinylpyrrolidone) (PNVP-NHBoc) required a two-step approach. 20 Then, PNVCL n -NHBoc (n = 66, 100) was treated with TFA to afford amino-terminated PNVCL (PNVCL n -NH 2 ). (c, d, e, f, g, h and i for the PNVCL block; w and o for the dendritic block) (Fig.…”

Section: Synthesis and Characterization Of Ldbcsmentioning

confidence: 99%

“…19 In addition, Phe-Lys dipeptides can be incorporated into the dendrons of amphiphilic linear-dendritic block copolymers (LDBCs) to obtain enzyme-responsive polymeric micelles. 20 As a polymer with the 'classical' Flory-Huggins thermoresponsive behavior (type I), poly(N-vinylcaprolactam) (PNVCL) has a lower critical solution temperature (LCST) near the physiological temperature. 21 Compared with poly(N-isopropylacrylamide), which has been widely studied, PNVCL is not hydrolyzed into small amine compounds, and PNVCL is nonionic, nontoxic and biocompatible.…”

Section: Introductionmentioning

confidence: 99%

Cathepsin B and thermal dual‐stimuli responsive linear‐dendritic block copolymer micelles for anticancer drug delivery

Song

Wei

et al. 2021

Polymer International

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In this study, two linear poly(N-vinylcaprolactam)s (PNVCLs) with different molecular weights were first synthesized as polymeric supporters by reversible addition-fragmentation chain transfer polymerization and then were used to prepare cathepsin B and thermal dual-stimuli responsive amphiphilic linear-dendritic block copolymers (LDBCs) PNVCL n -b-D(Phe-Lys) 1-3 (n = 66, 100) with linear PNVCL and dendritic phenylalanyl-lysine (Phe-Lys) dipeptides via stepwise peptide chemistry. The copolymers were characterized by 1 H NMR spectra and gel permeation chromatography and exhibited a controlled molecular weight and a narrow molecular weight distribution (polydispersity index ≤ 1.27). They self-assemble into stable micelles at relatively low critical micelle concentrations (0.007-0.019 mg mL −1 ) in aqueous solution. These micelles are capable of dissociating to release the encapsulated anticancer drug doxorubicin upon cathepsin B treatment. The doxorubicin release rates from PNVCL n -b-D (Phe-Lys) 1-3 micelles decreased with increasing generation of Phe-Lys dipeptide dendrons and decreasing molecular weight of PNVCL. In addition, the lower critical solution temperatures of the copolymers increased with an extension of the enzyme incubation time. The results of in vitro cytotoxicity and cell uptake experiments showed that LDBCs show no cytotoxicity even at a high LDBC concentration of 0.4 mg mL −1 and the drug-loaded micelles can be enriched in tumor cells. Such smart copolymers could be efficiently used in targeted therapy systems.

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“…From the described examples, it is clear that PEG has been mostly used as a linear block for the preparation of amphiphilic LDBCs [ 15 ] due to its biocompatibility and properties as a stealth coating polymer for biomedical applications [ 36 , 37 ]. However, alternatives such as poly[ N -(2-hydroxyethyl- l -glutamine)] [ 38 ] or poly( N -vinylpyrrolidone) [ 39 ] have also been investigated for this purpose.…”

Section: Introductionmentioning

confidence: 99%

Supramolecular Functionalizable Linear–Dendritic Block Copolymers for the Preparation of Nanocarriers by Microfluidics

et al. 2021

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Hybrid linear–dendritic block copolymers (LDBCs) having dendrons with a precise number of peripheral groups that are able to supramolecular bind functional moieties are challenging materials as versatile polymeric platforms for the preparation of functional polymeric nanocarriers. PEG2k-b-dxDAP LDBCs that are based on polyethylene glycol (PEG) as hydrophilic blocks and dendrons derived from bis-MPA having 2,6-diacylaminopyridine (DAP) units have been efficiently synthesized by the click coupling of preformed blocks, as was demonstrated by spectroscopic techniques and mass spectrometry. Self-assembly ability was first checked by nanoprecipitation. A reproducible and fast synthesis of aggregates was accomplished by microfluidics optimizing the total flow rate and phase ratio to achieve spherical micelles and/or vesicles depending on dendron generation and experimental parameters. The morphology and size of the self-assemblies were studied by TEM, Cryogenic Transmission Electron Microscopy (cryo-TEM), and Dynamic Light Scattering (DLS). The cytotoxicity of aggregates synthesized by microfluidics and the influence on apoptosis and cell cycle evaluation was studied on four cell lines. The self-assemblies are not cytotoxic at doses below 0.4 mg mL–1. Supramolecular functionalization using thymine derivatives was explored for reversibly cross-linking the hydrophobic blocks. The results open new possibilities for their use as drug nanocarriers with a dynamic cross-linking to improve nanocarrier stability but without hindering disassembly to release molecular cargoes.

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

Cited by 14 publications

References 48 publications

Amphiphilic Poly(N-vinylpyrrolidone) Nanoparticles Conjugated with DR5-Specific Antitumor Cytokine DR5-B for Targeted Delivery to Cancer Cells

Amphiphilic Poly(N-vinylpyrrolidone) Nanoparticles Conjugated with DR5-Specific Antitumor Cytokine DR5-B for Targeted Delivery to Cancer Cells

Cathepsin B and thermal dual‐stimuli responsive linear‐dendritic block copolymer micelles for anticancer drug delivery

Supramolecular Functionalizable Linear–Dendritic Block Copolymers for the Preparation of Nanocarriers by Microfluidics

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