Maxime Ranger

Novel Polymeric Micelles Based on the Amphiphilic Diblock Copolymer Poly(N-vinyl-2-pyrrolidone)-block-poly(D,L-lactide)

AbstractPurpose. The purpose of this work was to synthesize a new amphiphilic diblock copolymer of poly(N-vinyl-2-pyrrolidone and poly(D,L-lactide) (PVP-b-PDLLA) capable of self-assembling into polymeric micelles with multiple binding sites and high entrapment efficiency. Methods. The copolymer was synthesized by ring-opening polymerization of D,L-lactide initiated by potassium PVP hydroxylate. It was characterized by gel permeation chromatography, 1H- and 13C-NMR spectroscopy. The ability of the copolymer to self-assemble was demonstrated by dynamic and static light scattering, spectrofluorimetry and 1H-NMR. The hydrophobic model drug indomethacin was incorporated into the polymeric micelles by a dialysis procedure. Results. A series of amphiphilic diblock copolymers based on PVP-b-PDLLA were successfully synthesized. The critical association concentrations in water were low, always below 15 mg/L. Micellar size was generally bimodal with a predominant population between 40 and 100 nm. PVP-b-PDLLA micelles were successfully loaded with the poorly water-soluble drug indomethacin and demonstrated an entrapment efficiency higher than that observed with control poly(ethylene glycol)-b-PDLLA micelles. It was hypothesized that specific interactions with the hydrophilic outer shell could contribute to the increase in drug loading. Conclusion. PVP-b-PDLLA micelles appear to exhibit multiple binding sites and thus represent a promising strategy for the delivery of a variety of drugs.

A Novel One-Step Drug-Loading Procedure for Water-Soluble Amphiphilic Nanocarriers

AbstractPurpose. The lack of water-solubility hampers the use of many potent pharmaceuticals. Polymeric micelles are self-assembled nanocarriers with versatile properties that can be engineered to solubilize, target, and release hydrophobic drugs in a controlled-release fashion. Unfortunately, their large-scale use is limited by the incorporation methods available, especially when sterile dosage forms are sought. Methods. In this manuscript, we describe a straightforward, economical, and innovative drug-loading procedure that consists in dissolving both the drug and an amphiphilic diblock copolymer in a water/tert-butanol mixture that is subsequently freeze-dried. Results. We demonstrate that monodisperse 20-60 nm-sized drug-loaded polymeric micelles are produced directly and spontaneously upon rehydration of the freeze-dried cake. To establish the proof-of-principle, two hydrophobic taxane derivatives were solubilized in the micelles, and their partition coefficient was determined. Conclusions. This approach is efficient yet astonishingly simple and may be of great interest for scientists working in nanotechnology and pharmaceutical sciences.

Micelles in anticancer drug delivery

In recent years, the development of micelle-based carriers for cancer chemotherapy has been the object of growing scientific interest, both in academia and the pharmaceutical industry. Micelles have attracted attention in drug formulation and targeting, given that they provide a set of unique features. The core/shell structure accounts for their qualities as efficient drug delivery systems. The core provides a reservoir where hydrophobic drugs can be dissolved, and the corona confers hydrophilicity to the overall system. Sequestration of anticancer drugs in the inner core can protect them from premature degradation and allow their accumulation at tumoral sites.Micelles can be subdivided into two different groups according to their molecular weights: low-molecular-weight surfactant micelles and polymeric micelles. Although surfactant micelles such as polyethoxylated castor oil (e.g. Cremophor® EL) are commonly used to solubilize hydrophobic anticancer drugs such as paclitaxel, they have often been associated with serious adverse effects. Polymeric micelles may offer several advantages over surfactant micelles in terms of drug loading, adverse effects, stability, and targeting of tumors. Indeed, polymeric micelles can increase the circulation time of cytostatics and induce substantial changes in their biodistribution, including tumor accumulation via the enhanced permeation and retention effect. In addition, some recent studies have demonstrated that amphiphilic block copolymers (e.g. poloxamers) used for the preparation of polymeric micelles could increase the activity of several cytostatics by reversing multidrug resistance.This review first describes and compares surfactant micelle and polymeric micelle systems, already commercialized or under investigation, used to administer cytostatics. Secondly, their in vitro interactions with neoplastic cells and tissues are discussed in terms of cellular uptake and pharmacologic activity. In particular, the pharmacokinetics and biodistribution of micelles, along with the factors affecting their delivery to tumoral sites, are thoroughly discussed. Finally, in vivo studies reporting the anticancer activity and toxicity of drugs associated with micelles are reviewed.

Identification, characterization and potent antitumor activity of ECO-4601, a novel peripheral benzodiazepine receptor ligand

PurposeECO-4601 is a structurally novel farnesylated dibenzodiazepinone discovered through DECIPHER® technology, Thallion’s proprietary drug discovery platform. The compound was shown to have a broad cytotoxic activity in the low micromolar range when tested in the NCI 60 cell line panel. In the work presented here, ECO-4601 was further evaluated against brain tumor cell lines. Preliminary mechanistic studies as well as in vivo antitumor evaluation were performed.MethodsSince ECO-4601 has a benzodiazepinone moiety, we first investigated if it binds the central and/or peripheral benzodiazepine receptors. ECO-4601 was tested in radioligand binding assays on benzodiazepine receptors obtained from rat hearts. The ability of ECO-4601 to inhibit the growth of CNS cancers was evaluated on a panel of mouse, rat and human glioma cell lines using a standard MTT assay. Antitumor efficacy studies were performed on gliomas (rat and human), human breast and human prostate mouse tumor xenografts. Antitumor activity and pharmacokinetic analysis of ECO-4601 was evaluated following intravenous (IV), subcutaneous (SC), and intraperitoneal (IP) bolus administrations.ResultsECO-4601 was shown to bind the peripheral but not the central benzodiazepine receptor and inhibited the growth of CNS tumor cell lines. Bolus SC and IP administration gave rise to low but sustained drug exposure, and resulted in moderate to significant antitumor activity at doses that were well tolerated. In a rat glioma (C6) xenograft model, ECO-4601 produced up to 70% tumor growth inhibition (TGI) while in a human glioma (U-87MG) xenograft, TGI was 34%. Antitumor activity was highly significant in both human hormone-independent breast (MDA-MB-231) and prostate (PC-3) xenografts, resulting in TGI of 72 and 100%, respectively. On the other hand, IV dosing was followed by rapid elimination of the drug and was ineffective.ConclusionsAntitumor efficacy of ECO-4601 appears to be associated with the exposure parameter AUC and/or sustained drug levels rather than Cmax. These in vivo data constitute a rationale for clinical studies testing prolonged continuous administration of ECO-4601.

Conformational, optical and photophysical properties of a substituted terfluorene isolated and incorporated in a polyester

Abstract The optical and photophysical properties of a terfluorene, isolated and incorporated in a polyester, are reported. A similar oligofluorene having carboxylic acid groups at each end of the molecule has also been studied. This molecule provides a better correlation with its corresponding polyester. The fully relaxed single-bond torsional potentials of both oligofluorenes were evaluated with the aid of semiempirical calculations (AM1). The incorporation of the terfluorene in the polyester does not change its conformation and spectral properties. On the other hand, the luminescence intensity of the polyester ( φ f =0.76) is slightly weaker than that of the terfluorenes ( φ f =0.88 and 0.93) but remains intense.

Synthesis and characterization of a novel polyester derived from substituted terfluorene

Poly(1,6-hexane-9,9,9′,9′,9″,9″-hexahexyl-7,2′;7′,2″-terfluorene-2,7″-dicarboxylate) (PTFHHC6) has been synthesized and characterized. This polymer exhibits strong emission in the blue range, both in solution (quantum yield of 76%) and in the solid state. Moreover, PTFHHC6 presents some advantages over other polyfluorene derivatives since its solid-state fluorescence spectrum does not show any excimer formation and does not vary upon thermal treatment. Electrochemical measurements have revealed a reversible p-n dopable polymer. This aromatic polyester shows promising optical and electrical properties for the development of blue light-emitting diodes.

Synthesis and characterization of polyanilines with electron-withdrawing substituents

The synthesis of different homopolymers and copolymers derived from anilines bearing strong electron-withdrawing groups (-CF 3 , -CN, -NO 2 ) is reported It has been found that the oxidation of 3-substituted anilines leads to more regular polymers than those obtained from the 2-isomers. Protonation of suc substituted polyanilines is rendered difficult and can only occur at pH < 0. Copolymerization with unsubstituted aniline should give materials with modulation of the basicity, leading to localized charge carriers upon acid-doping. Electrical and optical properties of these copolymers will be reported.

2,7-Dibromo-9,9-dioctylfluorene–Chloroform (1/0.25)

In the solid state, the title compound, C29H40Br2.0.25CHCl3, crystallizes in the tetragonal system. The fluorene ring system is perfectly planar. The torsion angles in the octyl chains are all trans. These octyl chains are all orthogonal to the aromatic ring and are in the ab plane of the unit cell. The stacking of aromatic units is non-existent. In the cyclopentadiene ring, the angle at the benzilic carbon is 101.1 (3)° and is smaller than other angles in this part of the fluorene ring system.

Novel base-dopable poly(2,7-fluorenylene) derivatives

A novel acidic poly(fluorenylene) derivative has been synthesized which, upon base-doping, shows electrical conductivities of 10 - 6 –10 - 5 S cm - 1 ; this new doping method for conjugated polymers opens the way to the preparation of air-stable n-type conducting polymers.

Development of base-dopable polymers

Abstract A series of new well-defined acidic poly(2,7-fluorene) derivatives have been synthesized by palladium-catalyzed Suzuki couplings. Upon deprotonation (i.e. base-doping), these conjugated polymers generate stable polymeric anions counter-balanced by alkali metal cations. The resulting polymeric salts exhibit interesting electronic and/or ionic conducting properties. For instance, base-doped poly-2,7′-((4-hexylphenyl) 9,9-dioctyl-2′,7-bifluorene-9′-carbonyl) exhibits an electrical conductivity of 10 −2 – 10 −3 S/cm while poly-2,7′-((4-hexylphenyl) 9-isobutylidene-2′,7-bifluorene-9-carbonyl) shows an electrical conductivity up to 10 −1 S/cm in air, at room temperature. In the latter case, the high electrical conductivity is related to the good stability of the formed anions but also to the fact that all side chains are parallel to the plane of the polyfluorene backbone, leading to a more efficient interchain electrical transport. These attractive electrical properties confirm the great potential of these novel acidic fluorene-based π-conjugated polymers for various devices.