Azide-terminated Poly Research Articles

Fabrication of reduction-degradable micelle based on disulfide-linked graft copolymer-camptothecin conjugate for enhancing solubility and stability of camptothecin

This research is aimed to develop a reduction-degradable micelle delivery system based on polymer-camptothecin (CPT) conjugate in order to enhance the solubility and stability of CPT in aqueous media. Firstly, disulfide-linked poly(amido amine) (SS-PAA) containing alkyne groups was synthesized by Michael addition polymerization between propargyl amine and N,N′-bis(acryloyl) cystamine (BAC). And then, azide-functionalized CPT derivatives were conjugated with SS-PAA by click cycloaddition. Further grafting of residual alkyne groups in SS-PAA with azide-terminated poly(ethylene glycol) methyl ether (mPEG) gave mPEG-g-SS-PAA-CPT conjugate. At last, micelles with size of ca. 88 nm were fabricated from mPEG-g-SS-PAA-CPT conjugate, suggesting their passive targeting potential to tumor tissue. It was worthy of note that the drug-loaded system of mPEG-g-SS-PAA-CPT micelles improved the solubility and stability of CPT in aqueous media. Owing to the reduction degradability of disulfide linker in main chain of mPEG-g-SS-PAA-CPT, the CPT sustainably release from micelles together with the gradual cleavage of polymer in the presence of dithiothreitol (DTT) at the concentration of simulating the intracellular condition while almost no change occurred at the level of DTT corresponding to extracellular condition. Furthermore, the cell viability results showed the essential decrease of cytotoxicity to L929 cell line. These results present a strategy in designing anti-tumor CPT-polymer conjugates for highly selective delivery to tumor cells.

Nanomicelle with long-term circulation and enhanced stability of camptothecin based on mPEGylated α, β-poly ( l-aspartic acid)-camptothecin conjugate

To enhance the stability and long-term circulation of camptothecin (CPT), mPEGylated α, β-poly ( l-aspartic acid)-CPT conjugates were synthesized, and used to fabricate nanomicelle. Firstly, α, β-poly ( l-aspartic acid) derivative (PAA-der) containing alkyne groups was synthesized via the ring-opening of PSI with propargyl amine. And then, azide-functionalized CPT derivatives (CPT-N 3) and azide-terminated poly (ethylene glycol) methyl ether (mPEG-N 3) were conjugated with PAA-der by click cycloaddition to give mPEG- graft-PAA-CPT conjugates. The formation of mPEG- graft-PAA-CPT nanomicelles was confirmed by fluorescence spectrophotoscopy and particle size measurements. It was found that all the nanomicelles showed spherical shapes with size about 178 nm. MPEG- graft-PAA-CPT nanomicelles showed good storage stability, even incubation at 37 °C for 60 days, and improved the stability of CPT lactone form in aqueous media. A steady release rate of CPT was kept for 72 h, suggested the great potential of mPEG- graft-PAA-CPT nanomicelles as polymer prodrug of CPT.

Preparation of Polymers Containing Metal–Metal Bonds along the Backbone Using Click Chemistry

The [(η5-C5H4(CH2)3OC(O)(CH2)2C≡CH)Mo(CO)3]2 complex (1) was synthesized and used to explore the feasibility of using the Huisgen cycloaddition reaction (a click reaction) to incorporate molecules with metal–metal bonds into polymer backbones. In a model reaction, coupling of 1 with benzyl azide was observed in 24 h using Cp*Ru(PPh3)2Cl as a catalyst. In contrast, the reaction of 1 with benzyl azide using a CuBr/ligand catalyst (where the ligand is either PMDETA or bipyridine), resulted in disproportionation of the Mo–Mo unit in 1. Complex 1 was also coupled with telechelic azide-terminated polystyrene oligomers. With either the CuBr/PMDETA or CuBr/bipyridine catalyst, disproportionation of the Mo–Mo bonded unit occurred before complete coupling was observed. The reaction was also slow when the Cp*Ru(PPh3)2Cl catalyst was used; however, no disproportionation products were observed and a high molecular weight polymer (Mn = 120,000 g/mol) was produced. The Cp*Ru(PPh3)2Cl catalyst was also used to couple 1 with azide-terminated poly(ethylene glycol). After 15 h, this reaction produced a polymer with Mn = 73,000 g mol−1. It is concluded that, although somewhat slow, click chemistry using the Cp*Ru(PPh3)2Cl catalyst is an excellent method for synthesizing high molecular weight polymers with metal–metal bonds along the backbone.

The Effect of PEO Length on the Self-Assembly of Poly(ethylene oxide)−Tetrapeptide Conjugates Prepared by “Click” Chemistry

Two series of poly(ethylene oxide)-tetrapeptide conjugates have been prepared using a "Click" reaction between an alkyne-modified tetra(phenylalanine) or tetra(valine) and various azide-terminated poly(ethylene oxide) (PEO) oligomers. Three different PEO precursors were used to prepare these conjugates, with number-average molecular weights of 350, 1200, and 1800 Da. Assembly of mPEO-F4-OEt and mPEO-V4-OEt conjugates was achieved by dialysis of a THF solution of the conjugate against water or by direct aqueous rehydration of a thin film. The PEO length has a profound effect on the outcome of the self-assembly, with the F4 conjugates giving rise to nanotubes, fibers, and wormlike micelles, respectively, as the length of the PEO block is increased. For the V4 series, the propensity to form beta-sheets dominates, and hence, the self-assembled structures are reminiscent of those formed by peptides alone, even at the longer PEO lengths. Thus, this systematic study demonstrates that the self-assembly of PEO-peptides depends on both the nature of the peptides and the relative PEO block length.

Synthesis, Self-Assembly, and In Vitro Doxorubicin Release Behavior of Dendron-like/Linear/Dendron-like Poly(ε-caprolactone)-b-Poly(ethylene glycol)-b-Poly(ε-caprolactone) Triblock Copolymers

Dendron-like/linear/dendron-like poly(epsilon-caprolactone)-b-poly(ethylene glycol)-b-poly(epsilon-caprolactone) triblock copolymers with controlled molecular weights (M(n) = 9550-30 460) and low polydispersities were synthesized by a click conjugation between dendron-like poly(epsilon-caprolactone) and bifunctional azide-terminated poly(ethylene glycol) (copolymer yield = 56-89%). Their molecular structures and physicochemical and self-assembly properties were thoroughly characterized by means of FT-IR, (1)H NMR, multiangle laser light scattering coupled with gel permeation chromatography, differential scanning calorimetry, wide-angle X-ray diffraction, dynamic light scattering, and transmission electron microscopy. Using a nanoprecipitation method, these triblock copolymers self-assembled into spherical flower-like micelles with an average diameter of less than 50 nm in aqueous solution, and both the copolymer composition and the dendritic topology of the hydrophobic core had no apparent influence on the morphology of nanoparticles. The critical aggregation concentrations of these copolymers ranged from 0.034 to 0.048 mg/mL. However, the anticancer doxorubicin-loaded nanoparticles showed worm-like micelles similar to blank nanoparticles fabricated by a dialysis method, and the loaded doxorubicin drug hardly affected the final morphology of nanoparticles. Moreover, the doxorubicin-loaded nanoparticles fabricated from the dumbbell copolymer showed a higher drug loading efficiency of 18% and a longer drug-release time of 45 days than the linear counterpart. Consequently, this provides a versatile strategy not only for the synthesis of biodegradable and biocompatible dendron-like/linear/dendron-like triblock copolymers with dumbbell topology by using click chemistry but also for fabricating worm-like doxorubicin-loaded nanoparticles for anticancer drug release.

A General Methodology Toward Drug/Dye Incorporated Living Copolymer−Protein Hybrids: (NIRF Dye-Glucose) Copolymer−Avidin/BSA Conjugates as Prototypes

Azide-terminated poly(tert-butyl acrylate) was synthesized via atom transfer radical polymerization (ATRP). Subsequent deprotection was performed to yield poly(acrylic acid) (PAA) possessing a reactive chain-end. A one-pot sequential amidation of the PAA with the amine derivatives of a near-infrared fluorescent dye (ADS832WS) and glucose produced NIRF dye-incorporated water-soluble copolymers. End-group modifications were performed to produce alkyne/biotin-terminated copolymers which were further employed to generate dye-incorporated polymer-protein hybrids via the biotin-avidin interaction with avidin or "click" bioconjugation with azide-modified BSA. We have overcome two fundamental limitations in the synthesis of bioconjugates: (a) the basic restriction in the diversity of copolymers which can be synthesized for producing bioconjugates, (b) the limitation in the number of dyes/drug molecules that can be attached per protein molecule. The copolymers possessed enhanced optical properties compared to the dye due to increased solubility in water. Potential utility of these copolymers and conjugates in multiwell plate based assays, cell surface imaging and in vivo animal imaging were explored.

Covalently stabilized temperature and pH responsive four-layer nanoparticles fabricated from surface ‘clickable’ shell cross-linked micelles

Alkynyl-terminated double hydrophilic ABC triblock copolymer, poly(oligo(ethylene glycol) monomethyl ether methacrylate)-b-poly(2-(dimethylamino) ethyl methacrylate)-b-poly(2-(diethylamino) ethyl methacrylate) (alkynyl-POEGMA-b-PDMA-b-PDEA), was synthesized via atom transfer radical polymerization (ATRP) by sequential monomer addition using propargyl 2-bromoisobutyrate (PgBiB) as the initiator. The obtained triblock copolymer dissolves molecularly in acidic media and self-assembles into alkynyl surface-functionalized three-layer “onion-like” micelles consisting of a PDEA core, a PDMA inner shell, and a POEGMA corona at alkaline pH. Selective cross-linking of the PDMA inner shell with 2-bis(2-iodoethoxy)ethane (BIEE) results in structurally stable and surface ‘clickable’ shell cross-linked (SCL) micelles with pH-responsive PDEA cores. This new kind of SCL micelles could be further surface functionalized or conjugated with other azido- terminated polymer chains, functional groups, or biomolecules via Click chemistry. Four layer nanoparticles (SCL-PNIPAM) which have pH-responsive PDEA cores and temperature responsive PNIPAM outer coronas were fabricated from surface ‘clickable’ shell cross-linked (SCL) micelles and azide-terminated poly(N-isopropylacrylamide) (PNIPAM-N3) using Click chemistry. These novel four layer nanoparticles might act as suitable nano-sized drug delivery vehicles for the encapsulation and release of hydrophobic drugs as a function of either temperature or pH of the environment

Soluble Camptothecin Derivatives Prepared by Click Cycloaddition Chemistry on Functional Aliphatic Polyesters

Aliphatic polyesters are of interest as biomaterials and drug-delivery vehicles, as their ability to degrade under physiological conditions provides a mechanism for both drug release and clearance of the polymer from the body. Presented here is the synthesis of a polyester-drug graft copolymer conjugate, enabled by click cycloaddition of azide-functionalized camptothecin derivatives with alkyne-functionalized aliphatic polyesters. Further grafting of residual alkyne groups with azide-terminated poly(ethylene oxide) gave a water-soluble polyester-camptothecin conjugate. Control over PEGylation and drug loading, inherent to the graft copolymer design, opens versatile routes to new materials with potential utility in polymer therapeutics.