Polycaprolactone–b-poly(ethylene oxide) copolymer micelles as a delivery vehicle for dihydrotestosterone

Allen, Christine; Han, Jeannie; Yu, Yingning; Maysinger, Dušica; Eisenberg, Adi

doi:10.1016/s0168-3659(99)00200-x

Cited by 337 publications

(232 citation statements)

References 33 publications

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“…[9][10][11][12][13][14][15] These block copolymer micelles can be potentially used in specific biological and medical applications. [16][17][18] To obtain different micelle morphologies of block copolymers in solutions, two sets of parameters need to be taken into account. The first set consists of molecular parameters associated with the block copolymer itself, such as the chemical nature (hydrophobicity or hydrophilicity) of the blocks, the block and overall molecular weights, the miscibility of the blocks, and the block copolymer architectures (linear, star, graft, etc.).…”

Section: Introductionmentioning

confidence: 99%

Self‐assembled, wormlike‐cylinder network of polystyrene‐block‐poly(ethylene oxide) micelles in solution

Bhargava¹,

Zheng²,

Quirk³

et al. 2006

J Polym Sci B Polym Phys

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ABSTRACT:We report the formation of a highly entangled and interconnected, selfassembled, wormlike-cylinder network of polystyrene-block-poly(ethylene oxide) in N, N-dimethylformamide/water. In this system, N,N-dimethylformamide was a common solvent and water was a selective solvent for the poly(ethylene oxide) blocks. The degrees of polymerization of the polystyrene and poly(ethylene oxide) blocks were 962 and 227, respectively. The network was formed at copolymer concentrations higher than 0.4 wt % and consisted of self-assembled, wormlike cylinders that were interconnected by Y-shaped, T-shaped, and multiple junctions. The network morphology was visualized with transmission electron microscopy. Capillary viscometry measurements revealed an order-of-magnitude increase in the inherent viscosity of the colloidal system upon the formation of the network. A similar effort to obtain a wormlike-cylinder network in an N,N-dimethylformamide/acetonitrile system, in which acetonitrile was a selective solvent for the poly(ethylene oxide) blocks, was unsuccessful even at high copolymer concentrations; instead, the wormlike cylinders showed a tendency to align. The viscosity measurements also did not show a substantial increase in the inherent viscosity. Thus, the solvent played a critical role in determining the formation of the self-assembled, wormlike-cylinder network. This formation of the network resulted from an interplay between the end-capping energy, bending energy (curvature), and configurational entropy of the self-assembled, wormlike-cylinder micelles that minimized the free energy.

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Section: Introductionmentioning

confidence: 99%

Self‐assembled, wormlike‐cylinder network of polystyrene‐block‐poly(ethylene oxide) micelles in solution

Bhargava¹,

Zheng²,

Quirk³

et al. 2006

J Polym Sci B Polym Phys

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“…To minimize systemic toxicity due to the large volume of distribution associated with 17-DMAG, safer and more effective delivery of GA relies on the development of biocompatible delivery systems capable of solubilizing the drug and improving its pharmacokinetic properties. The utilization of selfassembled mPEG-b-PCL micelles has been effective at encapsulating other hydrophobic drug molecules for modifying pharmacokinetics and biodistributions [24,25,34]. In addition, there is literature precedence for synthesizing lipophilic prodrugs, such as daunorubicin or 5-fluorouracil, for increasing drug hydrophobicity and enhancing encapsulation into liposomal delivery systems [35][36][37].…”

Section: Discussionmentioning

confidence: 99%

“…The main disadvantage with micellar systems is that unstable micelles can fall apart rapidly in plasma leading to excessive drug loss [22]. However, the utilization of self-assembled diblock micelles of type AB, where A represents the methoxy-capped polyethylene glycol (mPEG) block and B represent the poly(ε-caprolactone) (PCL) block, termed mPEG-b-PCL, has been effective at encapsulating different hydrophobic drug molecules without the inclusion of potentially harmful surfactants and excipients such as CrEL or EtOH [23][24][25]. PCL is an extremely attractive polymer for drug delivery due to the biocompatible nature of the degradation products [26] and PCL is currently approved by the FDA for use in humans.…”

Section: Introductionmentioning

confidence: 99%

Formulation of a geldanamycin prodrug in mPEG-b-PCL micelles greatly enhances tolerability and pharmacokinetics in rats

Xiong

Yáñez

Remsberg

et al. 2008

Journal of Controlled Release

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Geldanamycin (GA) and its analogues inhibit heat shock protein 90 (Hsp90) and have shown significant antitumor activity in vivo; however, clinical development of GA has been hampered by its poor solubility and severe hepatotoxicity. More soluble analogues, such as 17-DMAG and 17-AAG, are easier to formulate, and have progressed through early clinical trials. However the large volume of distribution and systemic toxicity associated with these analogues may limit their distribution into tumors, thereby severely reducing efficacy and increasing nonspecific toxicities. We have evaluated a formulation of a lipophilic GA prodrug, 17′GAC 16 Br encapsulated in methoxycapped poly(ethylene glycol)-block-poly(ε-caprolactone) (mPEG-b-PCL) micelles, by comparing it to free 17-DMAG at 10 mg/kg in rats. mPEG-b-PCL micelles reported herein demonstrated substantial sustained release and conversion of 17′GAC 16 Br into 17′GAOH at significantly greater levels in all tissues analyzed compared to the free drug, allowing for a 72-fold enhancement in the AUC, a 21-fold decrease in V d , an 11-fold decrease in CL tot , and a 2-fold and 7-fold enhancement in the overall MRT of 17′GAC 16 Br and 17′GAOH, respectively. Importantly, the micellar formulation exhibited lower systemic toxicity than 17-DMAG, with a MTD > 200 mg/kg and a 2000-fold enhancement in the AUC. 17′GAC 16 Br in micelles were poorly cleared renally, in contrast to 17-DMAG and 17′GAOH, but showed preferential accumulation and prodrug conversion in reticuloendothelial organs of normal animals. Overall, the data indicates that this nanocarrier system is a promising alternative to the current 17-DMAG formulation and offers excellent potential for further pre-clinical and clinical cancer studies.

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“…Overall, they proved to be highly effective drug delivery vehicles [61][62][63][64][65]. To date, most contributions in the area of polymeric micelles for oral formulations, have been made by the group of Kabanov [66][67][68][69][70][71].…”

Section: Polymeric Micellesmentioning

confidence: 99%

Polymeric micelles for oral drug delivery: Why and how

Francis

Cristea

Winnik

2004

Pure and Applied Chemistry

166

100

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Abstract:The oral delivery of drugs is regarded as the optimal means for achieving therapeutic effects owing to increased patient compliance. Unfortunately, the oral delivery route is beset with problems such as gastrointestinal (GI) destruction of labile molecules, low levels of macromolecular absorption, etc. To reduce the impact of digestive enzymes and to ensure the absorption of bioactive agents in an unaltered form, molecules may be incorporated into microparticulate carriers. Many approaches to achieve the oral absorption of a wide variety of drugs are currently under investigation. Among the different polymer-based drug delivery systems, polymeric micelles represent a promising delivery vehicle especially intended for poorly water-soluble pharmaceutical active ingredients in order to improve their oral bioavailability. Recent findings of a dextran-based polymeric micelle study for solubilization of a highly lipophilic drug, cyclosporin A (CsA), will be discussed.

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Polycaprolactone–b-poly(ethylene oxide) copolymer micelles as a delivery vehicle for dihydrotestosterone

Cited by 337 publications

References 33 publications

Self‐assembled, wormlike‐cylinder network of polystyrene‐block‐poly(ethylene oxide) micelles in solution

Self‐assembled, wormlike‐cylinder network of polystyrene‐block‐poly(ethylene oxide) micelles in solution

Formulation of a geldanamycin prodrug in mPEG-b-PCL micelles greatly enhances tolerability and pharmacokinetics in rats

Polymeric micelles for oral drug delivery: Why and how

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