Nonionic Dendritic and Carbohydrate Based Amphiphiles: Self‐Assembly and Transport Behavior

Herein, a new series of non‐ionic dendritic and carbohydrate based amphiphiles is synthesized employing biocompatible starting materials and studied for supramolecular aggregate formation in aqueous solution. The dendritic amphiphiles 12 and 13 possessing poly(glycerol) [G2.0] as hydrophilic unit and C‐10 and C‐18 hydrophobic alkyl chains, respectively, exhibit low critical aggregation concentration (CAC) in the order of 10⁻⁵m and hydrodynamic diameters in the 8–10 nm range and supplemented by cryogenic transmission electron microscopy. Ultraviolet‐visible (UV‐Vis) and fluorescence spectroscopy suggests the effective solubilization of hydrophobic guests by the self‐assembled architectures, with the nanotransporters 12 and 13 possessing the highest encapsulation efficiency of 80.74 and 98.03% for curcumin. Efficient uptake of encapsulated curcumin in adenocarcinomic human alveolar basal epithelial (A549) cells is observed by confocal laser scanning microscopy. Amphiphiles 12 and 13 are non‐cytotoxic at the concentrations studied, however, curcumin encapsulated samples efficiently reduce the viability of A549 cells in vitro. Experimental studies indicate the ability of amphiphile 13 to encapsulate 1‐anilinonaphthalene‐8‐sulfonic acid (ANS) and curcumin with binding constant of 1.16 × 105⁵m ⁻¹ and 1.43 × 10⁶m ⁻¹, respectively. Overall, our findings demonstrate the potential of these dendritic amphiphiles for the development of prospective nanocarriers for the solubilization of hydrophobic drugs.     

Highly regioselective synthesis of amino-functionalized dendritic polyglycerols by a one-pot hydroformylation/reductive amination sequence

[reaction: see text] Dendritic architectures with neutral core structures and amines groups in the shell are a synthetic challenge, and there is a need for an efficient access. In this paper, highly selective Rh-catalysts are used for sequential hydroformylation/reductive amination of dendritic perallylated polyglycerols 1 with various amines in a one-pot procedure to give dendritic polyamines 3a-e in high yields (73-99%). In all cases, complete conversion of the allyl ether and aldehyde intermediate has been observed. Furthermore, the use of protected amines provides reactive core-shell-type architectures after deprotection. These soluble but membrane filterable multifunctional dendritic polyamines are of high interest as reagents in synthesis or as supports in homogeneous catalysis as well as nonviral vectors for DNA-transfection.     

Interactions between an anticancer drug and polymeric micelles based on biodegradable polyesters

Interactions between the anticancer drug quercetin and biodegradable polyesters within micelles were investigated by DSC, WAXD, and UV analyses. For micelles based on poly(ethylene glycol) methyl ether-block-poly(epsilon-caprolactone) (MPEG-PCL), DSC analysis indicated that the interactions were between the hydrophobic core and the drug within the micelle. For micelles based on poly(ethylene glycol) methyl ether-block-poly(L-lactide) (MPEG-PLLA), the interactions were between the hydrophobic core and the drug and between hydrophilic segments and the drug. WAXD results indicated that no crystalline phase of the drug was found in either of the micelle types. Based on the DSC and WAXD results, two probable micelle structures were proposed. The UV spectra revealed the presence of hydrogen bonding as the main interaction between the drug and the polyesters. In vitro studies demonstrated that quercetin release from micelles was sustained and was affected by the polymer-drug interaction.     

Syntheses and phase-transfer properties of dendritic nanocarriers that contain perfluorinated shell structures

Perfect dendrimers that contain perfluorinated shells have recently attracted attention because they have been shown to encapsulate polar molecules in supercritical CO(2) and catalytically active metal nanoparticles in perfluorinated solvents. Moreover, they can then be easily separated after reaction from the biphasic organic/fluorous system. In this paper several dendritic architectures that contain perfluorinated shells were derived by covalent modification of glycerol dendrimers ([G0.5]-[G3.5]), hyperbranched polyglycerol, and polyethyleneimine. These core-shell architectures show interesting physicochemical properties. For example, they are soluble in fluorinated solvents, they are able to transport different guest molecules, and they display thermomorphic behavior. The transport capacity of these molecular nanocarriers increases significantly when amino groups are present in the core. Certain functionalized polyethyleneimines that contain perfluorinated shells show high transport capacities (up to 3 dye molecules per nanocarrier) in perfluorinated solvents. Moreover, these perfluoro-functionalized dendritic polyethyleneimines can act as templates that stabilize nanoparticles; for example, encapsulation and subsequent chemical reduction of Ag(I) ions. Silver nanoparticles with a narrow size distribution (3.9+/-1 nm) have been prepared and characterized by transmission electron microscopy. Furthermore, it has been demonstrated that the encapsulated guest molecules remain accessible to small molecules after transport into the fluorous phase. Therefore, dendritic nanocarriers that contain perfluorinated shells are currently being investigated as polar environments in nonpolar reaction media such as fluorous phases and supercritical CO(2), in particular, for application in homogenous catalysis.     

Transport properties and aggregation phenomena of polyoxyethylene sorbitane monooleate (polysorbate 80) in pig gastrointestinal mucin and mucus

The aqueous environment in the gastrointestinal tract frequently requires solubilization of hydrophobic drug molecules in appropriate drug delivery vehicles. An effective uptake/absorption and systemic exposure of a drug molecule entails many processes, one being transport properties of the vehicles through the mucus layer. The mucus layer is a complex mixture of biological molecules. Among them, mucin is responsible of the gel properties of this layer. In this study, we have investigated the diffusion of polyoxyethylene sorbitane monooleate (polysorbate 80), a commonly used nonionic surfactant, in aqueous solution, in mucin solutions at 0.25 and 5 wt %, and in mucus. These measurements were done by using the pulsed field gradient spin echo nuclear magnetic resonance (PGSE-NMR) technique. We conclude that polysorbate 80 is a mixture of non-surface-active molecules that can diffuse freely through all the systems investigated and of surface-active molecules that form micellar structures with transport properties strongly dependent on the environment. Polysorbate 80 micelles do not interact with mucin even though their diffusion is hindered by obstruction of the large mucin molecules. On the other hand, the transport is slowed down in mucus due to interactions with other components such as lipids depots. In the last part of this study, a hydrophobic NMR probe molecule has been included in the systems to mimic a hydrophobic drug molecule. The measurements done in aqueous solution revealed that the probe molecules were transported in a closely similar way as the polysorbate 80 micelles, indicating that they were dissolved in the micellar core. The situation was more complex in mucus. The probe molecules seem to dissolve in the lipid depots at low concentrations of polysorbate 80, which slows down their transport. At increasing concentration of polysorbate 80, the diffusion of the probe molecules increases indicating a continuous dissolution of hexamethyldisilane in the core of polysorbate 80 micelles.     

Enhanced drug transport from unilamellar to multilamellar liposomes induced by molecular recognition of their lipid membranes

Unilamellar PC-based liposomes bearing a recognizable moiety were loaded either with the hydrophilic drug doxorubicin (DXR) or with the hydrophobic drug tamoxiphen (TMX) and allowed to interact with multilamellar PC-based liposomes bearing complementary recognizable groups. It has been established that, due to molecular recognition of these complementary liposomes, effective and fast transport of the drugs occurs from unilamellar to multilamellar liposomes. The transport of TMX is more effective compared to that of DXR. This behavior was observed for both PEGylated and non-PEGylated unilamellar liposomes, and it was attributed to the different sites of solubilization of the drugs in the unilamellar liposomes. PEGylation reduces the transport of both drugs since it inhibits to some extent the molecular recognition effectiveness of the complementary moieties.     

Experimental and theoretical investigation of the micellar-assisted solubilization of ibuprofen in aqueous media

Surfactants can be used to increase the solubility of poorly soluble drugs in water and to increase drug bioavailability. In this article, the aqueous solubilization of the nonsteroidal, antiinflammatory drug ibuprofen is studied experimentally and theoretically in micellar solutions of anionic (sodium dodecyl sulfate, SDS), cationic (dodecyltrimethylammonium bromide, DTAB), and nonionic (dodecyl octa(ethylene oxide), C12E8) surfactants possessing the same hydrocarbon "tail" length but differing in their hydrophilic headgroups. We find that, for these three surfactants, the aqueous solubility of ibuprofen increases linearly with increasing surfactant concentration. In particular, we observed a 16-fold increase in the solubility of ibuprofen relative to that in the aqueous buffer upon the addition of 80 mM DTAB and 80 mM C12E8 but only a 5.5-fold solubility increase upon the addition of 80 mM SDS. The highest value of the molar solubilization capacity (chi) was obtained for DTAB (chi = 0.97), followed by C12E8 (chi = 0.72) and finally by SDS (chi = 0.23). A recently developed computer simulation/molecular-thermodynamic modeling approach was extended to predict theoretically the solubilization behavior of the three ibuprofen/surfactant mixtures considered. In this modeling approach, molecular-dynamics (MD) simulations were used to identify which portions of ibuprofen are exposed to water (hydrated) in a micellar environment by simulating a single ibuprofen molecule at an oil/water interface (modeling the micelle core/water interface). On the basis of this input, molecular-thermodynamic modeling was then implemented to predict (i) the micellar composition as a function of surfactant concentration, (ii) the aqueous solubility of ibuprofen as a function of surfactant concentration, and (iii) the molar solubilization capacity (chi). Our theoretical results on the solubility of ibuprofen in aqueous SDS and C12E8 surfactant solutions are in good agreement with the experimental data. The ibuprofen solubility in aqueous DTAB solutions was somewhat overpredicted because of challenges associated with accurately modeling the strong electrostatic interactions between the anionic ibuprofen and the cationic DTAB. Our results indicate that computer simulations of ibuprofen at a flat oil/water interface can be used to obtain accurate information about the hydrated and the unhydrated portions of ibuprofen in a micellar environment. This information can then be used as input to a molecular-thermodynamic model of self-assembly to successfully predict the aqueous solubilization behavior of ibuprofen in the three surfactant systems studied.     

A convergent approach to biocompatible polyglycerol "click" dendrons for the synthesis of modular core-shell architectures and their transport behavior

Dendrimers are an important class of polymeric materials for a broad range of applications in which monodispersity and multivalency are of interest. Here we report on a highly efficient synthetic route towards bifunctional polyglycerol dendrons on a multigram scale. Commercially available triglycerol (1), which is highly biocompatible, was used as starting material. By applying Williamson ether synthesis followed by an ozonolysis/reduction procedure, glycerol-based dendrons up to the fourth generation were prepared. The obtained products have a reactive core, which was further functionalized to the corresponding monoazido derivatives. By applying copper(I)-catalyzed 1,3-dipolar cycloaddition, so-called "click" coupling, a library of core-shell architectures was prepared. After removal of the 1,2-diol protecting groups, water-soluble core-shell architectures 24-27 of different generations were obtained in high yields. In the structure-transport relationship with Nile red we observe a clear dependence on core size and generation of the polyglycerol dendrons.     

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(     

SOLUBILIZATION SITES AND ACID-BASE FORMS OF DIBUCAINE-HYDROCHLORIDE IN NEUTRAL AND CHARGED MICELLAR SOLUTIONS

Steady-state and time-resolved emission spectroscopic techniques have been employed to characterize the drug species of dibucaine and to identify its location in micellar Triton X-100 (neutral), hexadecyltrimethyl ammonium bromide (cationic) and lithium dodecyl sulfate (anionic) solutions at 77 K. Under physiological conditions, the dibucaine is shown to exist in the free base form (D) while solubilized in the hydrocarbon core of neutral micelles. In cationic micellar solution, dibucaine exists as the monocation species (DH+) where the anesthetic is solubilized in the extramicellar aqueous solution and D is solubilized in the hydrophobic region with close proximity to the micellar interface. In the anionic micelles, interfacial solubilization is most consistent with a site in which the tertiary amino group of the monocation dibucaine (DH+) is anchored at the micellar interface with its quinoline analog penetrating the hydrophobic region. The distinct properties observed for the drug species (i.e. D and DH+) and their solubilization sites in micelles are consistent with a balance between hydrophobic forces, surface polarity and the interfacial electrostatic potential present in the micellar solubilization sites. These observations could lend insight into the molecular basis of pharmacological action, in particular the mechanism of local anesthetic drug transport across membranes.     

Co-solubilization of the Hydrophobic Drugs Carbamazepine and Nifedipine in Aqueous Nonionic Surfactant Media

Co-solubilization of the hydrophobic drugs Carbamezipine (CBZ) and Nifedipine (NFD) by micellar solutions at 25 °C, using two series of polyoxyethylene based nonionic surfactants, was measured and compared. The first series is composed of surfactants with a 12 carbon (C₁₂) hydrophobic chain while the second series had 16 carbon (C₁₆) hydrophobic chains. Experimental results were obtained for solubilization and co-solubilization of CBZ and NFD within the micelles at saturation and quantification was done in terms of the molar solubilization ratio and the micelle–water partition coefficient employing spectrophotometric and tensiometric techniques. The extent of micellar solubilization of CBZ is much greater than NFD. The C₁₂ series of surfactants exhibit higher solubilization capacities for CBZ than the C₁₆ series while the reverse is the case for NFD. Co-solubilization results showed competitive solubilization of the drugs. A synergistic effect on the solubilization of NFD was observed in the presence of CBZ in Brij30 and Brij56 surfactant systems while, in the remaining surfactants, the solubility of NFD was slightly reduced. Since the surfactants used in the present study are either nontoxic or have minimal toxicity, it is expected that they can be employed as drug delivery vehicles for co-administration of the two drugs in vivo. Both from industrial and research points of view, this paper reports a comprehensive study for co-solubilization of differently structured drugs in micellar media.     

Polymeric conjugates for drug delivery

The field of polymer therapeutics has evolved over the past decade and has resulted in the development of polymer-drug conjugates with a wide variety of architectures and chemical properties. Whereas traditional non-degradable polymeric carriers such as poly(ethylene glycol) (PEG) and N-(2-hydroxypropyl methacrylamide) (HPMA) copolymers have been translated to use in the clinic, functionalized polymer-drug conjugates are increasingly being utilized to obtain biodegradable, stimuli-sensitive, and targeted systems in an attempt to further enhance localized drug delivery and ease of elimination. In addition, the study of conjugates bearing both therapeutic and diagnostic agents has resulted in multifunctional carriers with the potential to both "see and treat" patients. In this paper, the rational design of polymer-drug conjugates will be discussed followed by a review of different classes of conjugates currently under investigation. The design and chemistry used for the synthesis of various conjugates will be presented with additional comments on their potential applications and current developmental status.     

Membrane transport of a polyacid-tied doxorubicin

A model, based on fluorescence data, is developed for the poly(acrylic acid)-assisted transport of doxorubicin, a cationic antitumor drug, through a bilayer membrane. Accordingly, the doxorubicin binds to the poly(acrylic acid) via electrostatic polymer-drug interactions plus drug-drug stacking within the complex. This complex associates with neutral egg lecithin vesicles by means of hydrophobic attraction between the doxorubicin and the vesicle bilayers. In the process, the doxorubicin "destacks", providing a fluorescence change that can be monitored. Finally, the doxorubicin enters the vesicle interior which has been imparted with an acidic pH to protonate the doxorubicin and thus, in a second stage, yield an additional fluorescence change that can also be detected. A portion of the poly(acrylic acid), now devoid of doxorubicin, then leaves the outer vesicle surface and enters to external solution.     

Polymer-drug conjugates as inhalable drug delivery systems: A review

Accelerating interest by the pharmaceutical industry in the identification and development of less invasive routes of nanomedicine administration, coupled with defined efforts to improve the treatment of respiratory diseases through inhaled drug administration has fuelled growing interests in inhalable polymer-drug conjugates. Polymer-drug conjugates can alter the pharmacokinetic profile of the loaded drug after inhaled administration and enable the controlled and sustained exposure of the lungs to drugs when compared to the inhaled or oral administration of the drug alone. However, the major concern with the use of inhalable polymer-drug conjugates is their biocompatibility and long-term safety in the lungs, which is closely linked to lung retention times. A detailed understanding about the pharmacokinetics, lung disposition, clearance and safety of inhaled polymer-drug conjugates with significant translational potential is therefore required. This review therefore provides a comprehensive summary of the latest developments for several types of polymer-drug conjugates that are currently being explored as inhalable drug delivery systems. Finally, the current status and future perspective of the polymer-drug conjugates is also discussed with a focus on current knowledge gaps.     

芘在Pluronic两亲嵌段共聚物胶团中的增溶

用稳态荧光法研究芘（Py）在Pluronic两亲嵌段共聚物胶团水溶液中的增溶,结果表明共聚物分子中的PPO实际含量越大,越有利于Py的增溶。加入无机盐KCl导致生成了表面较少水化的较大胶团,并且由于KCl解离产生的离子使溶剂极性增加,这些因素促进了Py的增溶。     

Ultrafast fluorescence investigation of excitation energy transfer in different dendritic core branched structures

The mechanism of energy transport in branching structures is suggestively related to the geometry of the multichromophore architecture. In organic conjugated dendrimers, both incoherent (hopping) and coherent energy transfer processes have been observed from different dendritic architectures with different building blocks. In this communication, we report the investigation of three fundamental dendritic architectures (G0) with the same attached chromophores, but with different core atoms, C, N, and P. The synthesis of a phosphorus-containing G0 system with distyrylbenzene chromophores is provided. These three systems provide a comparison by which the relative interaction of branching chromophores can be compared on the basis of their different branching centers. Ultrafast fluorescence anisotropy measurements provide a dual measure of the geometry of the chromophores around the different central units as well as the strength of the interactions among chromophores. The nitrogen-cored system appeared to have both the strongest coupling of chromophore excitation as well as the most planar geometry of the three. Interestingly, the phosphorus system appeared to have the least planar geometry, and its interaction strength was found to be stronger than that observed for the carbon system. These results provide a comparison of the energy migration dynamics of the most common and new dendritic architectures with applications for light emission and light harvesting.     

聚乙二醇-聚磷酸酯嵌段共聚物的合成与性质以及对紫杉醇增溶作用的研究

合成了一系列甲氧基聚乙二醇(MPEG)和聚(2-甲氧基乙基亚乙基磷酸酯)(PMOEEP)的两嵌段聚合物MPEG-b-PMOEEP,并研究了该嵌段聚合物对疏水性化疗药物紫杉醇(PTX)的增溶效果.以MPEG为引发剂、异辛酸亚锡为催化剂,对五元环状磷酸酯单体2-甲氧基乙氧基-1,3,2-二氧磷杂环戊烷(MOEEP)进行开环...     

Hyperbranched‐upon‐dendritic macromolecules as unimolecular hosts for controlled release

Novel amphiphilic hyperbranched‐upon‐dendritic polymers with a dendritic polyester core, a linear poly(ε‐caprolactone) (PCL) inner shell, and a hyperbranched polyglycerol outer shell have been prepared. The structures of the hyperbranched‐upon‐dendritic polymers were characterized by using NMR spectra. The critical aggregating concentrations (CACs) of those amphiphilic hyperbranched‐upon‐dendritic polymers were measured by using pyrene as the polarity probe. To study the encapsulation performances of those hyperbranched‐upon‐dendritic polymers as unimolecular hosts, inter‐molecular encapsulation was carefully prevented by controlling the host concentrations below their CACs and by washing with good organic solvents. The study on encapsulation of two model guest molecules, pyrene and indomethacin, was performed. The amounts of encapsulated molecules were dependent mainly on the size of inner linear shells. About three pyrene molecules or five indomethacin molecules were encapsulated in hyperbranched‐upon‐dendritic polymers with average PCL repeating units of two but different hyperbranched polyglycerol outer shells, whereas about five pyrene molecules or about 12 indomethacin molecules were encapsulated in those with PCL repeating units of nine. The encapsulated molecules could be released in a controlled manner. Thus, the hyperbranched‐upon‐dendritic polymers could be used as unimolecular nanocarriers with controllable molecular encapsulation dosage for controlled release. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 4013–4019, 2010     

Low generational polyamidoamine dendrimers to enhance the solubility of folic acid:A‘‘dendritic effect’’investigation

Low generational(G0–G2,G for generation) polyamidoamine(PAMAM) dendrimers were investigated as enhancers to improve the aqueous solubility of folic acid at pH 11 and pH 5.In these two cases,the solubility of folic acid increases with both the dendrimer concentration and generation.However,the solubilization mechanism is different.The electrostatic interaction between the primary amines of dendrimers and the ionized carboxylic groups of folic acid dominates the dissolution process at pH 11 while the increase of the solubility of folic acid at pH 5 is attributed to the hydrophobic encapsulation inside the dendrimer molecules.In addition,for comparison ethylenediamine was used as a small molecule control to examine the ‘‘dendritic effect' in the dendrimer-related solubilization process.Interestingly,PAMAM dendrimers exhibit,at pH 5,a significant superiority over ethylenediamine in enhancing solubility,whereas this ‘‘dendritic effect' cannot be observed under the basic condition.     

New insights into the use of hydroxypropyl cellulose for drug solubility enhancement: An analytical study of sub-molecular interactions with fenofibrate in solid state and aqueous solutions

Hydroxypropyl cellulose (HPC) is a solubility enhancer used for poorly soluble drugs, nano-suspensions and amorphous solid dispersions (ASD). However, the underlying mechanism remains unclear. ASDs of a poorly soluble drug, fenofibrate (FEN), were analyzed using liquid nuclear magnetic resonance (NMR) and solid state NMR (ss-NMR). Liquid NMR revealed interactions between the pyranose ring of the HPC molecule and the diphenylketone from FEN. The water accessibility of the CH₃ groups in HPC and FEN is very low, they form a hydrophobic zone in aqueous solution that may sustain the drug nucleation. Moreover, ss-NMR measurements confirmed very low drug crystallinity for HPC-FEN ASDs. Cross-polarization and direct polarization ¹³C spectra, ¹³C-CPMAS and ¹³C-PARIS, distinguished the most rigid and flexible portions in concordance with the ss-NMR proton T₁ and T_1r relaxation results. Although HPC side chains (hydroxypropoxy) are the most flexible portions, their flexibility is moderate and high rigidity is the predominant. The ss-NMR proton relaxation indicates a rather homogeneous distribution of the components (HPC and FEN) in the solid mixtures. The versatile NMR methodology proposed can be used to study other polymer-drug systems and it may contribute to understand relevant functional aspects such as the rate of drug-delivery and their stability.