Cyclic Phosphate Monomers Research Articles

Accelerating the end-to-end production of cyclic phosphate monomers with modular flow chemistry.

The biocompatibility, tunable degradability and broad functionalities of polyphosphoesters and their potential for biomedical applications have stimulated a renewed interest from Chemistry, Medicinal Chemistry and Polymer Sciences. Commercial applications of polyphosphoesters as biomaterials are still hampered because of the time and resource-intensive sourcing of their corresponding monomers, in addition to the corrosive and sensitive nature of their intermediates and by-products. Here, we present a groundbreaking challenge for sourcing the corresponding cyclic phosphate monomers by a different approach. This approach relies on the use of continuous flow technologies to intensify the end-to-end preparation of cyclic phosphate monomers with a semi-continuous modular flow platform. The applied flow technology mitigates both safety and instability issues related to the more classical production of cyclic phosphate monomers. The first flow module allows safe synthesis of a library of cyclic chlorophosphite building blocks and features in-line 31P NMR real-time monitoring. After optimization on the microfluidic scale, this first module is successfully transposed toward mesofluidic scale with a daily throughput of 1.88 kg. Downstream of the first module, a second module is present, allowing the quantitative conversion of cyclic chlorophosphites with molecular oxygen toward chlorophosphate derivatives within seconds. The two modules are concatenable with a downstream semi-batch quench of intermediate chlorophosphate with alcohols, hence affording the corresponding cyclic phosphate monomers. Such a continuous flow setup provides considerable unprecedented advantages to safely and efficiently synthesize a library of versatile high value-added cyclic phosphate monomers at large scale. These freshly produced monomers can be successfully (co)polymerized, using either batch or flow protocols, into well-defined polyphosphoesters with assessed thermal properties and cytotoxicity.

Design of Degradable Polyphosphoester Networks with Tailor-Made Stiffness and Hydrophilicity as Scaffolds for Tissue Engineering.

In the recent decades, biodegradable and biocompatible polyphosphoesters (PPEs) have gained wide attention in the biomedical field as relevant substitutes for conventional aliphatic polyesters. These amorphous materials of low glass transition temperature offer promise for the design of soft scaffolds for tissue engineering. Advantageously, the easy variation of the nature of the lateral pendant groups of PPEs allows the insertion of pendent unsaturations valuable for their further cross-linking. In addition, varying the length of the pendent alkyl chains allows tuning their hydrophilicity. The present work aims at synthesizing PPE networks of well-defined hydrophilicity and mechanical properties. More precisely, we aimed at preparing degradable materials exhibiting identical hydrophilicity but different mechanical properties and vice versa. For that purpose, PPE copolymers were synthesized by ring-opening copolymerization of cyclic phosphate monomers bearing different pendent groups (e.g., methyl, butenyl, and butyl). After UV irradiation, a stable and well-defined cross-linked material is obtained with the mechanical property of the corresponding polymer films controlled by the composition of the starting PPE copolymer. The results demonstrate that cross-linking density could be correlated with the mechanical properties, swelling behavior, and degradation rate of the polymers network. The polymers were compatible to human skin fibroblast cells and did not exhibit significant cytotoxicity up to 0.5 mg mL-1. In addition, degradation products appeared nontoxic to skin fibroblast cells and showed their potential as promising scaffolds for tissue engineering.

ROS-responsive nanoparticles based on amphiphilic hyperbranched polyphosphoester for drug delivery: Light-triggered size-reducing and enhanced tumor penetration

Up to now, limited tumor penetration and poor therapeutic efficiency of drug-loaded nanoparticles are still the major challenges in nanomedicines for cancer chemotherapy. In photodynamic therapy, photosensitizers are often used to generate cytotoxic reactive oxygen species to kill cancer cells. Here, we report a kind of ROS-responsive nanoparticles with light-triggered size-reducing for enhanced tumor penetration and in vivo drug delivery to improve therapeutic efficiency. The nanoparticles were constructed by the self-assembly of an amphiphilic hyperbranched polyphosphoester containing thioketal units and photosensitizers, which is synthesized through the self-condensing ring-opening polymerization of a novel cyclic phosphate monomer and then end-capped with photosensitizer Chlorin e6. These nanoparticles have an initial averaged diameter of ∼210 nm, which can be used as drug carriers to load camptothecin with relatively stable in blood circulation. The CPT-loaded nanoparticles can be concentrated in tumor tissues through the long blood circulation and enhanced permeability and retention effect. Upon 660 nm laser irradiation on tumor tissues, the Ce6s in nanoparticles can effectively generate ROS to kill cancer cells meanwhile cleave the thioketal units to sequentially reduce the size of nanoparticles, which facilitate them more efficient tumor penetration with a programmable release of CPT. Both in vitro and in vivo studies confirmed the above results. Such ROS-responsive nanoparticles with light-triggered size-reducing provided a feasible approach to improve drug tumor penetration and achieve satisfied therapeutic efficacy.

Multifunctional Polymeric Prodrug with Simultaneous Conjugating Camptothecin and Doxorubicin for pH/Reduction Dual-Responsive Drug Delivery

Amphiphilic polymeric prodrugs show improved therapeutic indices with respect to traditional hydrophobic anticancer drugs because these prodrugs can self-assemble into nanoparticles, prolong the circulation of drugs in the blood, improve the accumulation of drugs in the disease site, reduce the side effects of drugs, and achieve therapeutic effect. Here, we describe a novel pH/reduction dual-responsive polymeric prodrug, abbreviated as CPT- ss-poly(BYP- hyd-DOX- co-EEP), with simultaneous conjugating camptothecin (CPT) and doxorubicin (DOX), wherein BYP and EEP represent two cyclic phosphate monomers, respectively, that is, 2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane and 2-ethoxy-2-oxo-1,3,2-dioxaphospholane. This prodrug was prepared through a polyphosphoester-DOX conjugate using a CPT derivative (CPT- ss-OH) as the initiator. CPT is linked to the terminal of polyphosphoester via disulfide carbonate, which is easy to break up under intracellular reductive environment and release the parent CPT, whereas DOX was efficiently incorporated onto the pendants of polyphosphoester through a hydrazone bond (- hyd-), which would be cleaved in the intracellular acidic medium. We show that the stable prodrug nanoparticles formed by self-assembly could release CPT and DOX simultaneously in the tumor microenvironment. The results of MTT assay demonstrate that the prodrug, which binds two antitumor drugs simultaneouly, has the properties of dual pH/reduction sensitiveness, biocompatibility, biodegradability, and effective tumor therapy.

Breathing air as oxidant: Optimization of 2-chloro-2-oxo-1,3,2-dioxaphospholane synthesis as a precursor for phosphoryl choline derivatives and cyclic phosphate monomers

Phosphoryl choline derivatives are important compounds for drug development. Also other phosphoesters have received increased demand in recent years. Many of such compounds rely 2-chloro-2-oxo-1,3,2-dioxaphospholane (COP) as an intermediate. COP is available in a two-step reaction from the cyclic adduct of phosphorus chloride and ethylene glycol after oxidation. Although commercially available, in-house synthesis of COP is often required due to pricing, purity, and delivery issues. Air is a convenient and economical oxidizing agent, yet not used for synthesis of COP. While slow consumption of the P(III)-precursor 2-chloro-1,3,2-dioxaphospholane with molecular oxygen from a gas bottle, high amounts of unreacted oxygen are lavished and even may cause an explosion. Oxygen from air is a reasonable and safer alternative. Additionally, catalytic amounts of cobalt(II)chloride increase the reaction kinetics remarkably. The results presented allow a controlled and fast access to a variety of phosphoesters by optimized reaction conditions of COP and its derivatives.

Novel ABC miktoarm star terpolyphosphoesters: Facile construction and high‐flame retardant property

ABSTRACTA combination of ring‐opening metathesis polymerization (ROMP), ring‐opening polymerization (ROP), and acyclic diene metathesis (ADMET) polymerization approach was first time utilized in the preparation of novel ABC miktoarm star terpolyphosphoesters (PPEs). Acrylate‐terminated monotelechelic PPE was first prepared through ROMP of 7‐membered cyclic phosphate monomer in the presence of a terminating agent, and then terminal acrylate group was readily converted, by thiol‐Michael addition click reaction and esterification, to a heterodifunctional PPE with hydroxyl and acrylate groups, which was a key precursor for the preparation of ABC miktoarm terpolymers. ROP of the cyclic phosphoester monomer initiated by this PPE was successively carried out to generate the acrylate‐functionalized block PPE, which utilized as a selective macromolecular chain stopper in subsequent ADMET polymerization of α,ω‐diene phosphate monomer, finally producing miktoarm terpolyphosphoester. These prepared miktoarm star terpolyphosphoesters demonstrated superior thermal and flame retardant properties via TGA, limiting oxygen index, and microscale combustion calorimetry tests. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 692–701

ChemInform Abstract: Hyperbranched Polyphosphates: Synthesis, Functionalization and Biomedical Applications

AbstractReview: 50 refs.

Synthesis of polyphosphodiesters by ring‐opening polymerization of cyclic phosphates bearing allyl phosphoester protecting groups

ABSTRACTThe allyl phosphoester group is shown to be a protecting group for the synthesis of anionic polyphosphodiesters. Our strategy relies on the synthesis of a cyclic phosphate monomer bearing a pendant allyl phosphoester group, its easy purification by fractional distillation, its organocatalyzed ring‐opening polymerization by 1,8‐diazobicyclo[5.4.0]undec‐7‐ene (DBU) and 1‐[3,5‐bis(trifluoromethyl)phenyl]‐3‐cyclohexyl‐thiourea (TU). Finally, the deprotection of the allyl phosphoester group is carried out by reaction with sodium benzenethiolate in the absence of any detectable degradation. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 2642–2648

One‐Pot Sequential Ring‐Opening Metathesis Polymerization and Acyclic Diene Metathesis Polymerization Synthesis of Unsaturated Block Polyphosphoesters

A novel divergent approach is presented for the one‐pot synthesis of unsaturated block poly­phosphoester (PPE) structures by a sequential ring‐opening metathesis polymerization (ROMP) and acyclic diene metathesis (ADMET) polymerization. A linear functional PPE bearing one or two terminal acrylate groups is first prepared through the third generation Grubbs catalyst‐mediated ROMP of seven‐membered cyclic phosphate monomer, in the presence of a symmetrical multifunctional terminating agent or chain transfer agent. The functional PPE is then utilized as a selective macromolecular chain stopper in subsequent ADMET polymerization of phosphoester functional asymmetric α,ω‐diene monomer, yielding unsaturated block PPEs. The thermal properties of block PPEs are studied and their thermal degradation and flame‐retardant properties are evaluated. Furthermore, the prepared block PPEs can spontaneously self‐assemble in a selective solvent to form polymeric micelles, which are characterized in detail by dynamic light scattering, atom force microscopy, transmission electron microscopy, and scanning electron microscopy analyses. image

Unsaturated poly(phosphoester)s via ring-opening metathesis polymerization

For the first time, ring-opening metathesis polymerization of novel 7-membered cyclic phosphate monomers and their copolymerization with cyclooctene is presented. The monomers were investigated with respect to their metathesis behavior with different Grubbs catalysts and it was found that the Grubbs third generation catalyst gives the best results resulting in polymers with a molecular weight of up to 5000 g mol−1. Also copolymers with cyclooctene (up to a molecular weight of ca. 50 000 g mol−1) were synthesized and the monomer ratios were varied. The degree of polymerization could be controlled and the polydispersity index was usually below two. Acidic hydrolysis of the copolymer showed a complete shift of the molecular weight distribution to higher elution times in SEC, indicating a random incorporation into the poly(cyclooctene) backbone of the phosphate monomers and the possible degradation of the phosphate bonds along the backbone. Further, potentially degradable nanoparticles were prepared by a solvent evaporation miniemulsion technique.

Metal-Free Strategies for the Synthesis of Functional and Well-Defined Polyphosphoesters

We report here metal-free strategies using organocatalysis based on supramolecular recognition for the ring-opening polymerization (ROP) of several cyclic phosphate monomers (CPMs) by a variety of organocatalysts such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5,7-triazabicyclo[4.4.0]undec-5-ene (TBD), and a bicomponent thiourea–tertiary amine catalyst. Each of these catalysts is efficient to produce linear polyphosphoesters (PPEs) from CPMs but with different sensitivity toward transesterification side reactions. The strong basicity of DBU is sufficient to activate an alcohol initiating the polymerization in the absence of any other cocatalyst. Nevertheless, side chain transfer reactions leading to branched and/or cyclic polymeric structures are observed, especially for high monomer conversion. Unlike DBU, TBD is a dual catalyst activating both the alcohol and the monomer. This dual activation allows shorter polymerization time, but SEC analyses of polyphosphates reveal bimodal molecular weight distr...

Micelles from Amphiphilic Block Copolyphosphates for Drug Delivery

Amphiphilic block copolyphosphates (PEP-b-PIPPs) are synthesized by two-step ROP of cyclic phosphate monomers with different pedant groups. They can spontaneously self-assemble into approximately spherical micelles ranging in size between 89 and 198 nm in water. A typical hydrophobic anti-cancer drug DOX is encapsulated into the micelles. The release rate of DOX slows down with increasing hydrophobic block length of PIPP. DOX-loaded micelles are investigated for the proliferation inhibition of Hela cells and the DOX dose required for 50% cellular growth inhibition is found to be 0.8 µg mL(-1). It is demonstrated that PEP-b-PIPP micelles can be used as a safe and promising drug delivery system.

Controlled Topological Structure of Copolyphosphates by Adjusting Pendant Groups of Cyclic Phosphate Monomers

A convenient method was reported to control the topological structure of copolyphosphates by adjusting the pendant group of cyclic phosphate monomers (CPMs) in the ring-opening polymerization (ROP), including linear block, star block, and hyperbranched multiarm structure. Linear block copolyphosphate (PEP-b-PIPP) was prepared by a two-step ROP procedure of CPMs with different pedant groups, i.e., monofunctional propargyl alcohol first initiated the ROP of the CPM with ethyl and then the CPM with isopropyl in turn. Similarly, star block copolyphosphate (SPEP-b-PIPP) was also synthesized when the monofunctional propargyl alcohol was replaced by a trifunctional trimethylolpropane. When the pendant group of CPM was changed into 2-hydroxyethyl, hyperbranched polyphosphate (HPHEP) was obtained first through the self-condensing ring-opening polymerization (SCROP) of such CPM, and then the terminal hydroxyls of HPHEP further initiated the ROP of CPM with ethyl to produce hyperbranched multiarm copolyphosphate (HPHEP-star-PEP). The resulting copolyphosphates were characterized by NMR, GPC, FTIR, and DSC techniques in detail, and the results confirmed their topological structures. Moreover, methyltetrazolium assay and AO/EB double staining methods indicated that all copolyphosphates with different topological structures had excellent biocompatibility against NIH 3T3 cells and would be applied as novel biomedical materials.