Recent advances of discrete coordination complexes and coordination polymers in drug delivery

Coordination complexes (including discrete coordination complexes and coordination polymers) have demonstrated excellent performance in drug delivery. This review outlines recent advances of discrete coordination complexes, bulk coordination polymers, and nanoscale/microscale coordination polymers in drug delivery. Specifically, rationale and mechanism of coordination complexes in drug delivery are summarized in this contribution. In this review, we discuss applications of these coordination species in drug delivery from perspectives in chemistry and pharmaceutical sciences, and an outlook of these coordination species of interest in drug delivery will also be proposed.     

Carrier polymers for cisplatin-type anticancer drug models

Following a brief discussion of the concept of polymer–drug conjugation and the use of platinum drugs in cancer therapy, the paper presents recent results in the synthesis of water-soluble polymeric carriers designed for the binding of antineoplastic coordination compounds of the cisplatin type. The target polymers, specifically, are linear aliphatic polyamides comprising the ethylenediamine ligand system in the main chain as the potential metal binding site. With solubility in aqueous media a key requirement for intravenously injectable conjugates, the polymers also contain hydrosolubilizing oligo(ethylene oxide) units in the chain, which serve the additional purpose of imparting resistance to serum protein binding and capture by the reticuloendothelial system. The synthesis methods include interfacial polymerization, high-temperature solution polycondensation in polyphosphoric acid and Michael addition polymerization, with 1,2-bis(2-aminoethylamino)ethane and 1,2-bis(3-aminopropylamino)ethane used as the amine comonomers providing the ethylenediamine ligand segment. The target polymers, crudely fractionated by dialysis in 25,000 molecular-mass cult-off tubing, are isolated by freeze-drying as water-soluble solids possessing inherent viscosities of 10–20 ml/g. A selected carrier polymer is converted to the corresponding water-soluble cis-diaminedichloroplatinum(II) conjugate by treatment with tetrachloroplatinate(II) anion in aqueous solution.     

Stimuli sensitive polymers for drug delivery systems

Temperature sensitive and electric field sensitive hydrogels were prepared for use in modulated drug release systems. Crosslinked poly(N-isopropyl-acrylamide) and its networks, modified with hydrophobic components by copolymerization or by interpenetrating polymer networks (IPNs) formation, were utilized as temperature sensitive hydrogels. Indomethacin (a model solute)-release from polymer matrix and permeation through polymer membrane demonstrated “on-off” regulation with temperature fluctuation. This was the result of polymer surface properties rather than bulk swelling, as temperature was changed past the swelling transition temperature range of the polymer. The on-off regulation in an electric field was also obtained with a positively charged solute (Edrophonium chloride) release in distilled-deionized water from a matrix of crosslinked poly(2-acrylamido-2-methylpropanesulfonic acid-co-butyl methacrylate). This was attributed to the ion exchange between Edrophonium ion and protons produced at the anode. The swelling changes produced by local pH or ionic strength changes affected non-charged solute release.     

Recombinant protein-based polymers for advanced drug delivery

Advances in recombinant techniques have led to the development of genetically engineered polymers with exquisite control over monomer sequence and polymer length. The ability to study how precise structures correlate with function has provided opportunities for the utility of these polymers in drug delivery. Chemically derived and developed methods of synthesis have yielded many useful polymers for drug delivery to-date, including those currently used in patients. However they have drawbacks, including limitations involved in statistical characterization of conventional polymer synthetic techniques. Encoding at the genetic level and production of such recombinant polymers in organisms allow for precise order and accuracy of amino acid residues and production of monodisperse polymers with specific function and physicochemical properties. Research into elastin-like, silk-like, and silk-elastinlike protein polymers for example has led to the development of delivery systems based on natural motifs of structural proteins to take advantage of their physicochemical properties. Additionally, protein based polymers on other natural motifs and de novo designs are starting to produce promising constructs for drug and gene delivery applications where precise control over structure promises correlation with function and guides the development of new and improved constructs. Clinical applications based on recombinant polymers for delivery of bioactive agents have not been realized at this point. However lessons learned from fundamental research with these polymers can be used to guide design of safe and effective systems for use in the clinic. This tutorial review summarizes progress made in the design and utility of recombinant polymers in drug and gene delivery and discusses challenges and future directions of such polymers for this purpose.     

Coordination bonding based pH-responsive albumin nanoparticles for anticancer drug delivery

Zn-loaded bovine serum albumin nanoparticles (Zn-BSA nanoparticles) were prepared and used as carriers for pH-responsive anticancer drug delivery. Zinc was introduced into this system to increase the stability of the BSA nanoparticles and to load the anticancer drug based on the coordination bonding formation of Zn-BSA and Zn-drug molecules, respectively. The cleavage of either the "Zn-BSA" or the "Zn-drug" coordination bonding, in response to pH, would result in the release of the drug under designated pH conditions. The nanoparticles were spherical with diameters of 50-60 nm and narrow size distribution. Mitoxantrone (MX) was chosen as the model drug to study the release behavior and the inhibitory efficacy against tumor cells. In vitro release behavior of MX loaded Zn-BSA nanoparticles (MX-Zn-BSA nanoparticles) showed a fine pH-responsiveness. The release amount at pH 5.0 was close to 80%, while the cumulative release amount at pH 7.4 was less than 6% within 24 h. The blank Zn-BSA nanoparticles were of low cytotoxicity, while a high cytotoxic activity of MX-Zn-BSA nanoparticles against MCF-7 cells was demonstrated by in vitro cell assays.     

Tailor-made dual pH-sensitive polymer-doxorubicin nanoparticles for efficient anticancer drug delivery

Efficient delivery of therapeutics into tumor cells to increase the intracellular drug concentration is a major challenge for cancer therapy due to drug resistance and inefficient cellular uptake. Herein, we have designed a tailor-made dual pH-sensitive polymer-drug conjugate nanoparticulate system to overcome the challenges. The nanoparticle is capable of reversing its surface charge from negative to positive at tumor extracellular pH (～6.8) to facilitate cell internalization. Subsequently, the significantly increased acidity in subcellular compartments such as the endosome (～5.0) further promotes doxorubicin release from the endocytosed drug carriers. This dual pH-sensitive nanoparticle has showed enhanced cytotoxicity in drug-resistant cancer stem cells, indicating its great potential for cancer therapy.     

Zwitterionic polymers: Addressing the barriers for drug delivery

Nanocarriers play an important role in drug delivery for disease treatment. However, nanocarriers face a series of physiological barriers after administration such as blood clearance, nonspecific tissue/cell localization, poor cellular uptake, and endosome trapping. These physiological barriers seriously reduce the accumulation of drugs in target action site, which results in poor therapeutic efficiency. Although polyethylene glycol (PEG) can increase the blood circulation time of nanocarriers, its application is limited due to the “PEG dilemma”. Zwitterionic polymers have been emerging as an appealing alternative to PEG owing to their excellent performance in resisting nonspecific protein adsorption. Importantly, the diverse structures bring functional versatility to zwitterionic polymers beyond nonfouling. This review focuses on the structures and characters of zwitterionic polymers, and will discuss and summarize the application of zwitterionic polymers for drug delivery. We will highlight the strategies of zwitterionic polymers to address the physiological barriers during drug delivery. Finally, we will give some suggestions that can be utilized for the development of zwitterionic polymers for drug delivery. This review will also provide an outlook for this field. Our aim is to provide a comprehensive and systemic review on the application of zwitterionic polymers for drug delivery and promote the development of zwitterionic polymers.     

Hydrolysis process of the second generation platinum-based anticancer drug cis-amminedichlorocyclohexylamineplatinum(II)

The hydrolysis process of the anticancer drug cis-amminedichlorocyclohexylamineplatinum(II) (JM118 or cis-[PtCl2(NH3)cyclohexylamine]) and the influence of solvent models therein have been studied using hybrid density functional theory (B3LYP). The aquation reactions leading to the activated drug forms a key step for the reaction with the target DNA. In this study, the stepwise hydrolysis, cis-[PtCl2(NH3)cyclohexylamine] + 2 H2O --> cis-[Pt(NH3)cyclohexylamine(OH2)2]2+ + 2 Cl- was explored, using three different models. Implicit solvent effects were incorporated through polarized continuum models. The stationary points on the potential energy surfaces for the first and second hydrolysis steps, proceeding via a general S(N)2 pathway, were fully optimized and characterized. It was found that the explicit solvent effects originating from the inclusion of extra water molecules into the system are significantly stronger than those arising from the bulk aqueous medium, especially for the second aquation step, emphasizing the use of appropriate models for these types of problems. In comparison with previous work on the parent compound cisplatin, a slower rate of hydrolysis is determined for the first (rate determining) reaction. The results furthermore imply that the doubly aquated form of JM118 will be the main DNA binding form of the drug. The results provide detailed energy profiles for the mechanism of hydrolysis of JM118, which may assist in understanding the reaction mechanism of the drug with the DNA target and in the design of novel Pt-containing anticancer drugs.     

Novel nanogels as drug delivery systems for poorly soluble anticancer drugs

Two types of novel nanogels were prepared using shell cross-linking of Pluronic F127 micelles with polyethylenimine (PEI) (F127/PEI nanogel), and penetrating network of poly(butylcyanoacrylate) (PBCA) in Pluronic F127 micelles (F127/PBCA nanogel). Poorly soluble anticancer drug, paclitaxel (PTX) and 10-hydroxycamptothecin (HCPT), were used as model drugs and incorporated into nanogels. The results obtained from FT-IR spectroscopy confirmed that the drugs were molecularly dispersed in the nanogels. DLS measurements demonstrated that the nanogel size distribution was narrow with average diameter less than 200 nm. TEM images indicated that the nanogels were spherical in shape and had smooth surfaces. The drug-loaded nanogels showed sustained release profiles compared with the free drugs as revealed by in vitro release experiments. Cytotoxicity tests showed that the cytotoxicity of drug-loaded nanogels against cancer cell in vitro was much higher than that of the free drug. The data demonstrate that these novel nanogels improved stability towards dilution, increased solubility and showed better cellular uptake by cells compared with free drug.     

pH-sensitive supramolecular copolydendrimers,new anticancer drug delivery system

In this work, new class of supramolecular copolydendrimers (SCDs) consisting of polyamidoamines (PAMAMs) and polyglycerol were synthesized through host-guest interactions. SCDs were able to encapsulate, transport, and release doxorubicin (DOX) efficiently. Host-guest interactions between PAMAM and polyglycerol was depended on pH so that aqueous solutions of SCDs and SCDs-based drug delivery systems were stable at room temperature and pH?=?7.4, but their building blocks were separated in lower pHs(     

Synthesis of self-assemble pH-responsive cyclodextrin block copolymer for sustained anticancer drug delivery

Well-defined p H-responsive poly(ε-caprolactone)-graft-β-cyclodextrin-graft-poly(2-(dimethylamino)ethylmethacrylate)-co-poly(ethylene glycol) methacrylate amphiphilic copolymers(PCL-g-β-CD-g-P(DMAEMA-co-PEGMA)) were synthesized using a combination of atom transfer radical polymerization(ATRP),ring opening polymerization(ROP) and "click" chemistry.Successful synthesis of polymers was confirmed by Fourier transform infrared spectroscopy(FTIR),proton nuclear magnetic resonance(1H-NMR),and gel permeation chromatography(GPC).Then,the polymers could selfassemble into micelles in aqueous solution,which was demonstrated by dynamic light scattering(DLS) and transmission electron microscopy(TEM).The p H-responsive self-assembly behavior of these copolymers in water was investigated at different p H values of 7.4 and 5.0 for controlled doxorubicin(DOX) release,and these results revealed that the release rate of DOX could be effectively controlled by altering the p H,and the release of drug loading efficiency(DLE) was up to 88%(W/W).CCK-8 assays showed that the copolymers had low toxicity and possessed good biodegradability and biocompatibility,whereas the DOX-loaded micelles remained with high cytotoxicity for He La cells.Moreover,confocal laser scanning microscopy(CLSM) images revealed that polymeric micelles could actively target the tumor site and the efficient intracellular DOX release from polymeric micelles toward the tumor cells further confirmed the anti-tumor effect.The DOX-loaded micelles could easily enter the cells and produce the desired pharmacological action and minimize the side effect of free DOX.These results successfully indicated that p H-responsive polymeric micelles could be potential hydrophobic drug delivery carriers for cancer targeting therapy with sustained release.     

Catechol polymers for pH-responsive, targeted drug delivery to cancer cells

A novel cell-targeting, pH-sensitive polymeric carrier was employed in this study for delivery of the anticancer drug bortezomib (BTZ) to cancer cells. Our strategy is based on facile conjugation of BTZ to catechol-containing polymeric carriers that are designed to be taken up selectively by cancer cells through cell surface receptor-mediated mechanisms. The polymer used as a building block in this study was poly(ethylene glycol), which was chosen for its ability to reduce nonspecific interactions with proteins and cells. The catechol moiety was exploited for its ability to bind and release borate-containing therapeutics such as BTZ in a pH-dependent manner. In acidic environments, such as in cancer tissue or the subcellular endosome, BTZ dissociates from the polymer-bound catechol groups to liberate the free drug, which inhibits proteasome function. A cancer-cell-targeting ligand, biotin, was presented on the polymer carriers to facilitate targeted entry of drug-loaded polymer carriers into cancer cells. Our study demonstrated that the cancer-targeting drug-polymer conjugates dramatically enhanced cellular uptake, proteasome inhibition, and cytotoxicity toward breast carcinoma cells in comparison with nontargeting drug-polymer conjugates. The pH-sensitive catechol-boronate binding mechanism provides a chemoselective approach for controlling the release of BTZ in targeted cancer cells, establishing a concept that may be applied in the future toward other boronic acid-containing therapeutics to treat a broad range of diseases.     

Study on surfactant coating of polymeric nanoparticles for controlled delivery of anticancer drug

Biodegradable nanoparticles loaded with anticancer drug paclitaxel and appropriately coated with polyvinyl alcohol (PVA), polyethylene glycol (PEG) as well as d--tocopheryl polyethylene glycol 1000 succinate (TPGS) were produced and characterised by various analysis techniques such as laser light scattering (LLS) for particle size and size distribution, scanning electron microscopy (SEM) and atomic force microscopy (AFM) for particle morphology, X-ray photoelectron spectroscopy (XPS) and Fourier Transform Infrared-Photoacoustic Spectroscopy (FTIR-PAS) for surface chemistry, and high performance liquid chromatography (HPLC) for drug encapsulation efficiency (EE) and in vitro release kinetics. The emphasis was given to the possible effects of surface coating on the physicochemical and pharmaceutical properties of paclitaxel loaded nanoparticles. It was found that the type and amount of the surfactant could significantly affect the drug EE in the nanoparticles, the particles characteristics and their in vitro release behaviour. The surfactants dominated on the nanoparticles surface and the coated nanoparticles displayed in spherical shape with relative smooth surface within the resolution scope of the equipment. The particle size and size distribution showed close relation to the surface coating, which may also be responsible for the drug encapsulation efficiency and the in vitro release kinetics. A favourable formulation of drug loaded nanoparticles of desired properties could be obtained by optimising the fabrication parameters.     

杂环反铂(Ⅱ)抗癌药物水解反应机理的DFT研究

用DFT-B3LYP方法和IEF-PCM溶剂化模型研究了反铂抗癌药物trans-[PtCl2(piperidine)(Am)](Am=2-picoline(1),3-picoline(2),4-picoline(3)),trans-[PtCl2(piperidine)(piperazine)](4),trans-[PtCl2(pipera-zine)2](5)and trans-[PtCl2(iminoether)2](6)的水解过程.水解反应是药物与DNA靶分子作用的关键活化步骤.全优化和表征了一水解和二水解反应经由一般的SN2路径过程所有物种的势能面稳定点.结果发现反应过程遵循已经建立的平面正方形配合物的配体取代反应理论,即取代反应通常通过一个三角双锥过渡态结构的铂配体交换反应发生.得到的过渡态结构与以前的相关工作一致,所有反应都是吸热反应;所有体系的二水解能垒都高于一水解.与顺铂相比,这些配合物都有更快的水解反应速率;并与以前类似的反铂配合物的研究做了比较.研究结果提供了这些配合物水解反应过程的详细能量变化,对理解药物与DNA靶分子的作用机理和新型反铂抗癌药物的设计有帮助.     

Overview on natural hydrophilic polysaccharide polymers in drug delivery

Nanotechnology is poised to make potentially revolutionary innovations in areas of biomedical science, such as gene therapy and drug therapy. A recently developed nanodelivery strategy involves the use of hydrophilic polymers as carriers of proteins and siRNA. By controlling the reaction conditions during polymer production, various degrees of anionic charge, cationic charge, and cross‐linking can be added, thereby changing their capabilities as protein and nucleic acid carriers and promoting effective cell membrane permeation. The efficiency of a specific controlled‐release polymeric system is determined in part by its unique physical and chemical properties and biodegradation rate. In this review, we will summarize recent progress in the ability to modify drug release of hydrophilic polymers nanoparticles.     

Dendritic polymers: from efficient catalysis to drug delivery

Dendritic polymers constitute an intriguing class of macromolecules that offer tremendous potential in designing new materaisl for applications in areas such as catalysis and small molecule loading and delivery. Synthesis of a variety of dendritic polymers using a simple and highly versatile synthetic methodology has enabled us to carry out a detailed investigation of dendritic effects in transition metal catalyzed organic transformations. Small dye molecules such as p-nitroaninline and DR1 could be loaded into the intrinsic cavities of the backbone of 3,5-dihydroxybenzyl alcohol based dendrimers, leading to a change in physical properties of both the dye and the dendrimer. We are also exploring the use of dendrimers as templates to prepare network carriers containing cavities of predetermined size and disposition.     

Rational design of multi-targeting ruthenium- and platinum-based anticancer complexes

Platinum-based anticancer drugs, including cisplatin and its analogues, have played important roles in the clinical treatment of solid tumors over the past 38 years. However, poor selectivity, high toxicity and intrinsic or acquired drug resistance profoundly limit their application, which encourages the development of novel transition metal-based anticancer agents with different mechanisms of action. To this end, transition metal complexes that can simultaneously act on more than one target, termed as single-molecule multi-targeting complexes, have attracted increasing attention because of their enhanced efficacy and diminished chance of drug resistance. In this review, we systematically discuss the recent progress in the development of platinum- and ruthenium-based anticancer agents, in particular the rational design of platinum and ruthenium complexes with multi-targeting features.