Synthesis and characterization of nanosized poly(organophosphazenes) with methoxy-poly(ethylene glycol) and dipeptide ethyl esters as side groups

Nanosized water soluble poly(organophosphazenes) were synthesized by grafting hydrophilic methoxy poly(ethylene glycols) and hydrophobic dipeptide ethyl esters as side groups to the phosphazene backbone. Their hydrodynamic volume could be controlled in the range of 10-30 nm in diameter depending on the length of the side groups and the molecular weight of the polymers. These polymers exhibited a lower critical solution temperature in the range of 60-105 °C and hydrolytic degradability, which can afford applications to a variety of drug delivery systems. The hydrolytic properties of the present poly(organophosphazenes) have been studied at 37 °C in different pH buffer solutions by means of gel permeation chromatography. The polymers substituted with the more hydrophobic and more bulky dipeptide groups caused slower hydrolysis and the polymer hydrolysis occurred more rapidly in the acidic buffer solution than in the neutral and basic solutions.     

Polyphosphazenes: Synthesis—properties—applications

Various aspects of polyphosphazene chemistry are reviewed. Stable poly (organophosphazenes) can be prepared from an inorganic precursor, poly(dichlorophosphazene), by careful control of polymerization and substitution reaction conditions. The bulk structure and properties of polyphosphazenes are discussed, and attention is given to those polymers which have promise as useful engineering materials. The successful preparation of stable poly(organophosphazenes) appears to have resulted in a new class of polymers for both specialty and large scale commercial development.     

Current Trends and Future Prospects of Molecular Targeted Therapy in Head and Neck Squamous Cell Carcinoma

In recent years, advances in drug therapy for head and neck squamous cell carcinoma (HNSCC) have progressed rapidly. In addition to cytotoxic anti-cancer agents such as platinum-based drug (cisplatin and carboplatin) and taxane-based drugs (docetaxel and paclitaxel), epidermal growth factor receptor-tyrosine kinase inhibitors (cetuximab) and immune checkpoint inhibitors such as anti-programmed cell death-1 (PD-1) antibodies (nivolumab and pembrolizumab) have come to be used. The importance of anti-cancer drug therapy is increasing year by year. Therefore, we summarize clinical trials of molecular targeted therapy and biomarkers in HNSCC from previous studies. Here we show the current trends and future prospects of molecular targeted therapy in HNSCC.     

Synthesis and characterization of thermosensitive poly(organophosphazene) gels with an amino functional group

Thermosensitive poly(organophosphazene) gels have been synthesized with a host of side groups, including α‐amino‐ω‐methoxy‐poly(ethylene glycol), hydrophobic amino acid esters (PheOEt, LeuOEt, and IleuOEt), depsipeptide ethyl ester (GlyGlycOEt), and lysine ethyl ester (lysOEt). The fraction of the last side group, lysOEt, which possesses two amine functional groups, was designed to be in the range of 0.1–0.3 mol per polymer unit. The poly(organophosphazenes) have been characterized via ¹H‐ and ³¹P‐NMR spectroscopies, GPC, and elemental analysis. The phase transition behavior of the poly(organophosphazenes) in aqueous solution has been determined via viscometry. Some of the poly(organophosphazenes) with amino functional groups exhibit reversible sol–gel transitions at temperatures near those of the human body, when in aqueous solution. These polymers form a sol at lower temperatures, and become gels at higher temperatures. Also, these polymer solutions have been found to behave generally like Newtonian fluids in the sol state, but appear to exhibit pseudoplastic qualities in the gel state. The polymers possessing depsipeptide ethyl esters (ethyl‐2‐(O‐glycyl)glycolate) as a side group tend to exhibit much higher degradation rates under physiological conditions than do those which lack the depsipeptide ethyl ester group. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci 120:998–1005, 2011     

Combining PARP Inhibition with Platinum,Ruthenium or Gold Complexes for Cancer Therapy

Platinum drugs are heavily used first-line chemotherapeutic agents for many solid tumours and have stimulated substantial interest in the biological activity of DNA-binding metal complexes. These complexes generate DNA lesions which trigger the activation of DNA damage response (DDR) pathways that are essential to maintain genomic integrity. Cancer cells exploit this intrinsic DNA repair network to counteract many types of chemotherapies. Now, advances in the molecular biology of cancer has paved the way for the combination of DDR inhibitors such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) and agents that induce high levels of DNA replication stress or single-strand break damage for synergistic cancer cell killing. In this review, we summarise early-stage, preclinical and clinical findings exploring platinum and emerging ruthenium anti-cancer complexes alongside PARPi in combination therapy for cancer and also describe emerging work on the ability of ruthenium and gold complexes to directly inhibit PARP activity.     

SISO-based hot-melt pressure-sensitive adhesives for transdermal delivery of hydrophilic drugs

A monomer-activated anionic polymerization approach was utilized to synthesize poly(styrene-b-isoprene-b-styrene-b-ethylene oxide) tetrablock terpolymers (SISO), which were melt-mixed with tackifiers and plasticizer to develop polar SISO-based hot-melt pressure-sensitive adhesives (HMPSAs) for transdermal delivery of hydrophilic drugs. Their hydrophilic performance was characterized using contact angle analysis. Their adhesive performances were measured in terms of 180° peel strength and holding power. In vitro drug release experiments were carried out using a modified Franz type horizontal diffusion cell, in which geniposide was chosen as a hydrophilic model drug. The results show that poly(ethylene oxide) (PEG) blocks exhibit substantial effects on adhesive performance and the release behavior of the model drug. The shorter PEG molecular chains enhance adhesive performance and the cumulative release rate of the model drug in the SISO-based HMPSAs. The longer PEG molecular chains tend to crystallize. Their crystallization structures have negative effects on adhesive performance and limit the dissolution and diffusion of drugs in the SISO-based HMPSAs. Therefore, appropriate PEG molecular chains are required to fabricate SISO-based HMPSAs with excellent adhesive performance for transdermal delivery of hydrophilic drugs.     

Gas Diffusion and Solubility in Poly(organophosphazenes): Results of Molecular Simulation Studies

A combination of quantum chemistry, molecular dynamics, and Monte Carlo methods have been used to investigate gas diffusion and solubility in three isomeric poly[di(butoxyphosphazenes)] and in amorphous and crystalline states of poly[bis(2,2,2-trifluoroethoxyphosphazene)] (PTFEP). In this review of recently published studies reported from our laboratory, conclusions are reached in regards to the relationship between polymer structure and gas diffusion and sorption in poly(organophosphazenes). These conclusions also serve to validate our current understanding of the nature of gas transport in other polymers. Specifically, gas diffusivity has been shown to increase with increasing side-chain and main-chain mobility as determined from vectorial autocorrelation function analysis; however, high diffusivity is accompanied by a loss in diffusive selectivity resulting in decreasing permselectivity with increasing permeability. Simulation of crystalline supercells of PTFEP indicate that gas diffusion is unrestricted in the crystalline state as has been reported only for a few other polymers, principally poly(4-methyl-1-pentene). Gas solubility in poly(organophosphazenes) correlates well with gas condensability as measured by the Lennard–Jones potential well depth parameter, ɛ/k. Exceptions are cases where specific interactions can occur between gas molecules and the polymer chain such as is the case of CO₂ and PTFEP. High-level ab initio calculations of the interaction of CO₂ with low-molecular-weight fluoroalkanes indicate the presence of a weak quadrupole–dipole interaction. Association of CO₂ with the trifluoromethyl groups of the trifluoroethoxy side chain of PTFEP has been confirmed by radial distribution function (RDF) analysis of MD trajectories. Comparison between solubility coefficients obtained from Grand Canonical Monte Carlo (GCMC) simulations of amorphous cells with experimental values of microcrystalline PTFEP indicates that gas solubility in polyphosphazenes such as PTFEP that exhibit a mesophase/crystalline state is greatly reduced. This paper is dedicated to Prof. Harry Allcock for his scientific contributions to inorganic and organometallic polymers.     

Synthesis and characterization of biodegradable thermosensitive neutral and acidic poly(organophosphazene) gels bearing carboxylic acid group

The needs to develop thermosensitive biodegradable polymers have been raised in the area of injectable polymer therapeutics. The aims of this work are to develop thermosensitive biodegradable poly(organophosphazene) gels having functional group and characterize their physicochemical properties such as thermosensitivity and hydrolytic behaviors. Controlled thermosensitivity and hydrolytic degradability of polymer gels were obtained with randomly grafted amphiphilic poly(organophosphazenes). Hydrophobic L-isoleucine ethyl ester (IleOEt) and hydrophilic poly(ethylene glycol) 550 or 750 Da (PEG 550 or 750) were substituted along with relatively small amount of glycylglycine allyl ester (GlyGlyOALL) which was deprotected into glycylglycine (GlyGlyOH). By this procedure several neutral (GlyGlyOALL) and acidic (GlyGlyOH) poly(organophosphazene) pairs with same substituent ratio were prepared, in which the ratio of substituent groups could systematically modulate their thermosensitive properties. The aqueous solutions and gels of prepared acidic poly(organophosphazene) also showed the thermosensitive sol-gel transition and biodegradation at body temperature, respectively. Acidic poly(organophosphazene) exhibited much faster hydrolytic degradation than neutral polymer in the buffer solutions (pH 7.4) at 37 °C. With systematically regulated thermo-responsiveness and hydrolytic degradability, the synthesized poly(organophosphazenes) are expected to be smart injectable materials having a useful moiety and further chemically conjugated with various bioactive molecules for biomedical applications.     

Review of Multifarious Applications of Poly (Lactic Acid)

Poly (lactic acid) is considered to be a promising alternative to petroleum-based polymers due to its renewability, biodegradability, biocompatibility, and good mechanical properties. Because of the high cost, the applications of poly (lactic acid) were limited to the medical field. Over the past decade, improvements in polymerization allow the economical mass production of high molecular weight poly (lactic acid). Therefore, the applications of poly (lactic acid) have recently spread to domestic, commercial packaging, and textile applications. This review outlines the chemical, thermal characteristics of poly (lactic acid) and discusses the use of poly (lactic acid) in medical applications such as sutures, stents, drug carrier, orthopaedic devices, scaffolds, as well as commercial applications in textile and packaging fields with superior properties such as high wicking performance, good dyeability, antibacterial feature, good ultraviolet resistance, high water vapor transmission rates, shrink wrapping, and dead fold property. While the drawbacks of poly (lactic acid) utilized in these fields are also discussed. It is clear that the advantages of using poly (lactic acid) outlined in this review will ensure that the market for poly (lactic acid) products will continue to expand.     

pH‐sensitive hydroxyethyl starch–doxorubicin conjugates as antitumor prodrugs with enhanced anticancer efficacy

Doxorubicin (DOX) is a widely used chemotherapeutic drug for the treatment of several types of cancers, which has limitation in clinical applications because of severe heart toxicity. Herein, to reduce the fast clearance from the blood system and the severe systemic toxicity caused by the nonspecific protein adsorption, a pH‐sensitive drug delivery system with higher drug conjugated content was prepared by conjugating DOX onto hydroxyethyl starch (HES) with a pH‐sensitive hydrazone bond. In normal physiological environment, the release of DOX conjugated onto HES was slight which could be neglected without any side effect. However, in an acidic environment mimicking the tumor microenvironment, this pH‐sensitive hydrazone linkage provided a controlled and sustained release of DOX over a period of more than 3 days. The conjugates had good biocompatibility, long circulation, and lower cytotoxicity, which could efficiently be transferred into HeLa and HepG2 cells and release the conjugated drug. Based on these promising properties, these HES–DOX conjugates outline the significant potential for future biomedical application in the controlled release of antitumor drugs. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42778.     

Injectable and thermosensitive poly(organophosphazene) hydrogels for a 5‐fluorouracil delivery

The drug solubility and its release profiles of an anticancer drug from an injectable thermosensitive poly(organophosphazene) hydrogel bearing hydrophobic L ‐isoleucine ethyl ester and hydrophilic α‐amino‐ω‐methoxy‐poly(ethylene glycol) with and without hydrolysis‐sensitive glycyl lactate ethyl ester or functional glycyl glycine have been investigated. 5‐Fluorouracil (5‐FU) was used as a model anticancer drug. The aqueous solutions of 5‐FU incorporated poly(organophosphazenes) were an injectable fluid state at room temperature and formed a transparent gel at body temperature. The poly(organophosphazene) solution could enhance the solubility of 5‐FU and its solubility (34.26 mg/mL) was increased up to 10‐fold compared to that in phosphate‐buffered saline (3.39 mg/mL, pH 7.4, 4°C). The in vitro drug release profiles from poly(organophosphazene) hydrogels were established in phosphate‐buffered saline at pH 7.4 at 37°C and the release of 5‐FU was significantly affected by the diffusion‐controlled stage. The results suggest that the injectable and thermosensitive poly(organophosphazene) hydrogel is a potential carrier for 5‐FU to increase its solubility, control a relatively sustained and localized release at target sites and thus decrease systemic side effects. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Controlled co‐delivery of hydrophilic and hydrophobic drugs from thermosensitive and crystallizable copolymer nanoparticles

Functionalized amphiphilic block copolymers poly(N‐isopropyl acrylamide)‐b‐poly(stearyl methacrylate) (PNIPAM‐PSMA) are synthesized. Their self‐assembled core‐shell nanoparticles have the hydrophilic thermosensitive shell and hydrophobic crystallizable core. Nanoparticles exhibit volume phase transition at temperature of 38 °C and its poly(stearyl methacrylate) (PSMA) moiety could form nano size crystals to retain drugs, making them good carriers for drug co‐delivery system. Thermosensitivity and crystallinity of nanoparticles are characterized with dynamic light scattering (DLS), differential scanning calorimetry (DSC), small‐angle X‐ray scattering (SAXS), and atomic force microscopy (AFM). The interactions and relationship between chemical structures of copolymer nanoparticles and loading drugs are discussed. Different loading techniques and combined loading of hydrophobic/hydrophilic drugs are studied. Nanoparticles show a good and controllable drug loading capacity (DL) of hydrophilic/hydrophobic drugs. The drugs release kinetics is analyzed with Fick's law and Weibull model. A general method for analyzing drug release kinetics from nanoparticles is proposed. Weibull model is well fitted and the parameters with definite physical meaning are analyzed. PNIPAM‐PSMA nanoparticles show a quite different thermal response, temporal regulation, and sustained release effect of hydrophilic and hydrophobic drugs, suggesting a promising application in extended and controlled co‐delivery system of multi‐drug. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 44132.     

ABC block copolymer as “smart” pH-responsive carrier for intracellular delivery of hydrophobic drugs

Amphiphilic triblock copolymer of poly(ethylene glycol)-block-poly(dimethylaminoethyl methacrylate)-block-poly(ε-caprolatone) (PEG-PDMA-PCL) was synthesized using a one-pot sequential oxyanionic polymerization of DMA and ε-CL, associated with a PEG-O⁻K⁺ macroinitiator. The pH-responsive micellization behavior of the copolymer was studied using dynamic light scattering (DLS), steady-state fluorescence and TEM techniques. The anti-cancer drug of doxorubicin (DOX) was chosen as a model drug to investigate the potential application of this triblock copolymer in drug controlled release. The results indicated the important roles of the PCL block for drug loading, the PDMA block for pH-responsive release, and PEG block for good bio-affinity. Cell cytotoxicity tests showed that the DOX-loaded PEG-PDMA-PCL micelles were pharmaceutically active to suppress the growth of SKOV-3 cells. This novel stimuli-responsive block copolymer is an attractive candidate as the “smart” pH-responsive carrier for intracellular delivery of hydrophobic drugs.     

Functional polypeptide and hybrid materials: Precision synthesis via α-amino acid N-carboxyanhydride polymerization and emerging biomedical applications

Polypeptides derived from naturally occurring α-amino acids have emerged as a unique and versatile family of bio-inspired biomaterials that can be tailor-made for varying biomedical applications such as controlled drug release, gene delivery, tissue engineering and regenerative medicine. In contrast to traditional biodegradable polymers such as aliphatic polyesters and polycarbonates, polypeptides are inherently functional, allow precise control over polarity and charges, show excellent stability against hydrolysis, and are prone to rapid biodegradation in vivo by specific enzymes. Ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydrides (NCAs) is the most straightforward and practical approach for large-scale production of high molecular weight polypeptides. In the past decade, a remarkable progress has been made in controlled NCA polymerization, which offers an unprecedented access to precision polypeptide and hybrid materials by combining with living radical polymerization, click chemistry, and/or post-polymerization modification. Notably, several micellar anti-cancer drugs based on poly(ethylene glycol)-polypeptides have been already advanced to the clinical evaluation. In this review paper, we give an overview on de novo design, controlled synthesis and emerging biomedical applications of functional polypeptide and hybrid materials.     

Modeling the Accumulation of Degradable Polymer Drug Carriers in the Brain

The blood–brain barrier (BBB) limits the access of drugs to the brain. Intensive research is being conducted on the development of nanoparticulate drug carriers that mediate transfer across the BBB. A question that has been neglected so far is the potential accumulation of the carrier in the brain upon long‐term exposure. Here, we address this question by implementing a kinetic model to relate drug loading, required concentration of drug in the brain, and drug clearance to the degradation half‐life of the carrier. As a test case with clinical relevance we chose poly‐lactic‐co‐glycolic‐acid (PLGA) as a carrier material and a chemotherapeutic for which the required parameters could be recovered from the literature. For methotrexate with a drug load of 8.5 %, a required concentration of free drug of 1 μm , a release from PLGA of 6 hours, a drug clearance from the brain of 3 hours and a half‐life of polymer degradation of 28 days, a steady‐state accumulation of 1.3 g polymer would be reached in the brain (1.5 L) after seven months. While this number is surprisingly small, further physiological research is warranted to assess to which degree this will be in a tolerable range.     

Photochemistry and photophysics of poly(organophosphazenes) and related compounds: A review. III. Applicative aspects

In the third part of this review we report some applicative aspects of poly(organophosphazenes) in photochemical fields. In particular, the possible application of phosphazene polymers that contain azobenzene or spiropyran residues as photochromic macromolecules is outlined; the light-induced grafting of organic, carbon-backboned polymers onto polyphosphazene matrices, as a method of modifying both surface and bulk properties of these materials, is highlighted; and the potential application of cyclophosphazenes as photo-stabilizers for commercial organic polymers or as photoinitiators for radical polymerization of vinyl monomers is described.Parts I and II in this series appeared in this journal, Volume 4, Numbers 1 and 2, 1994, respectively.     

Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance

Histone deacetylases (HDACs) regulate gene expression through the epigenetic modification of chromatin structure. HDAC6, unlike many other HDACs, is present in the cytoplasm. Its deacetylates non-histone proteins and plays diverse roles in cancer cell initiation, proliferation, autophagy, and anti-cancer drug resistance. The development of HDAC6-specific inhibitors has been relatively successful. Mechanisms of HDAC6-promoted anti-cancer drug resistance, cancer cell proliferation, and autophagy are discussed. The relationship between autophagy and anti-cancer drug resistance is discussed. The effects of combination therapy, which includes HDAC6 inhibitors, on the sensitivity of cancer cells to chemotherapeutics and immune checkpoint blockade are presented. A summary of clinical trials involving HDAC6-specific inhibitors is also presented. This review presents HDAC6 as a valuable target for developing anti-cancer drugs.     

Photochemistry and photophysics of poly(organophosphazenes) and related compounds: A review. II. Bimolecular reactions

In the second part of this review we highlight the bimolecular reactions (hydrogen abstraction, and energy or electron transfer) that take place in the photochemistry of poly(organophosphazenes). Both inter-molecular interactions (i.e. between excited free chromophores and ground state groups attached to the phosphazenes, or between excited phosphazene substituents and external quenchers) and intra-molecular processes (i.e. between excited and ground state groups geminally attached to the same phosphorus or supported to different phosphorus along the polyphosphazene skeleton) are exploited. Suggestions are given on the possible practical application of these reactions in different photochemical domains, e.g. heterogeneous-phase photosensitization, photocrosslinking, photoconductivity, microelectronics, light-induced radical polymerization of vinyl monomers, etc.     

Significance and strategies in developing delivery systems for bio-macromolecular drugs

Successful development of a new drug is prohibitively expensive, and is estimated to cost approximately $100–500 million US dollars for a single clinical drug. Yet, a newly developed drug can only enjoy its patent protection for 18 years, meaning that after this protected time period, any company can manufacture this product and thus the profit generated by this drug entity would reduce dramatically. Most critically, once a drug is being synthesized, its physical, chemical, and biological attributes such as bioavailability and in vivo pharmacokinetics are all completely fixed and cannot be changed. In principal and practice, only the application of an appropriately designed drug delivery system (DDS) is able to overcome such limitations, and yet the cost of developing a novel drug delivery system is less than 10% of that of developing a new drug. Because of these reasons, the new trend in pharmaceutical development has already begun to shift from the single direction of developing new drugs in the past to a combined mode of developing both new drugs and innovative drug delivery systems in this century. Hence, for developing countries with relatively limited financial resources, a smart strategic move would be to focus on the development of new DDS, which has a significantly higher benefit/risk ratio when comparing to the development of a new drug. Because of the unmatched reaction efficiency and a repetitive action mode, the therapeutic activity of a single bio-macromolecular drug (e.g., protein toxins, gene products, etc.) is equivalent to about 10⁶–10⁸ of that from a conventional small molecule anti-cancer agent (e.g., doxorubicin). Hence, bio-macromolecular drugs have been recognized around the world as the future “drug-of-choice”. Yet, among the>10000 drugs that are currently available, only ~150 of them belong to these bio-macromolecular drugs (an exceedingly low 1.2%), reflecting the difficulties of utilizing these agents in clinical practice. In general, the bottleneck limitations of these bio-macromolecular drugs are two-fold: (1) the absence of a preferential action of the drug on tumor cells as opposed to normal tissues, and (2) the lack of ability to cross the tumor cell membrane. In this review, we provide strategies of how to solve these problems simultaneously and collectively via the development of innovative drug delivery systems. Since worldwide progress on bio-macromolecular therapeutics still remains in the infant stage and thus open for an equal-ground competition, we wish that this review would echo the desire to industrialized countries such as China to set up its strategic plan on developing delivery systems for these bio-macromolecular drugs, thereby realizing their clinical potential.