Delivery of HSP90 Inhibitor Using Water Soluble Polymeric Conjugates with High Drug Payload.


PURPOSE:HSP90 (Heat shock protein 90kD) has been validated as a therapeutic target in Castrate Resistant Prostate Cancer. Unfortunately, HSP90 inhibitors suffer from dose-limiting toxicities that hinder their clinical applications. Previously developed polymeric delivery systems for HSP90 inhibitors had either low drug content or low biological activity suggesting the need for better delivery system for HSP90 inhibitors. METHODS:We developed a simplified synthetic strategy to prepare polyethylene glycol based water-soluble polymeric system for model HSP90 inhibitor geldanamycin (GDM). We then investigated the effect of cathepsin B degradable linker and drug content in polymeric conjugates on their growth inhibitory property using DU145 (androgen independent) and LNCaP (androgen dependent) cell lines. RESULTS:Water-soluble polymeric conjugates were synthesized with GDM content ranging from 9 to 30% wt/wt. We demonstrated the importance of cathepsin B degradable linker from the context of drug content and different prostate cancer cell lines. The most active conjugate against DU145 cells exhibited IC50 value of 2.9 μM. This was similar to the IC50 (2.1 μM) of small molecular drug aminohexane geldanamycin. CONCLUSION:Water-soluble polymeric conjugate with high drug content was synthesized that exhibited in-vitro growth inhibitory activity similar to small molecular weight HSP90 inhibitor. Graphical Abstract Water soluble degradable polymeric conjugate for the delivery of Geldanamycin.


Pharm Res


Pharmaceutical research


Suárez Del Pino JA,Kolhatkar R




Has Abstract


2017-12-01 00:00:00














  • Binding and uptake of wheat germ agglutinin-grafted PLGA-nanospheres by caco-2 monolayers.

    abstract:PURPOSE:The Caco-2 association of lectin-grafted PLGA-nanospheres was investigated compared to plain and BSA-coated spheres. METHODS:Nanospheres made from fluorescent-labeled PLGA were coated with wheat germ agglutinin (WGA) or BSA and incubated with Caco-2 monolayers varying the concentration of nanospheres, the time...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Weissenboeck A,Bogner E,Wirth M,Gabor F

    更新日期:2004-10-01 00:00:00

  • Including information on the therapeutic window in bioequivalence acceptance.

    abstract:PURPOSE:A novel bioequivalence limit is proposed taking into account the therapeutic window. METHODS:The therapeutic range is introduced as the ratios maximum tolerated dose/therapeutic dose (MTD/D) and the therapeutic dose/lowest effective dose. The performance of the new acceptance range was compared with the method...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Jacobs T,De Ridder F,Rusch S,Van Peer A,Molenberghs G,Bijnens L

    更新日期:2008-11-01 00:00:00

  • Structure-activity relationships for substrates and inhibitors of mammalian liver microsomal carboxylesterases.

    abstract:PURPOSE:Carboxylesterases are important in the detoxification of drugs, pesticides and other xenobiotics. This study was to evaluate a series of substrates and inhibitors for characterizing these enzymes. METHODS:A series of novel aliphatic esters and thioesters were used in spectral assays to monitor human, murine an...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Huang TL,Shiotsuki T,Uematsu T,Borhan B,Li QX,Hammock BD

    更新日期:1996-10-01 00:00:00

  • In situ intestinal absorption of a poorly water-soluble drug from mixed micellar solutions of bile salt and lipolysis products in rats.

    abstract::The role of a bile salt (sodium taurocholate) and lipolysis products (monoglyceride and fatty acid) in the intestinal absorption of a poorly water-soluble drug, diazepam, was investigated. Absorption rates and bioavailabilities were determined with the in situ rat gut technique of Doluisio et al. and analyzing the dia...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Serajuddin AT,Rosoff M,Goldberg AH

    更新日期:1985-09-01 00:00:00

  • Prodrugs of peptides. 11. Chemical and enzymatic hydrolysis kinetics of N-acyloxymethyl derivatives of a peptide-like bond.

    abstract::Various carboxylic acid esters of the N-hydroxymethyl derivative of N-benzyloxycarbonylglycine benzylamide, used as a peptide-like model, were prepared and their decomposition kinetics studied in aqueous solution and in human plasma solutions. These N-acyloxymethylamide derivatives were found to undergo a facile decom...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Bundgaard H,Rasmussen GJ

    更新日期:1991-10-01 00:00:00

  • Adhesion of powders for inhalation: an evaluation of drug detachment from surfaces following deposition from aerosol streams.

    abstract:PURPOSE:To evaluate micronized powder retention and detachment from inhaler surfaces following reproducible deposition by impaction, coupled with centrifugal particle detachment (CPD). METHODS:Micronized albuterol sulfate (AS) and beclomethasone dipropionate (BDP) were aerosolized as dry powders and deposited by casca...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Clarke MJ,Peart J,Cagnani S,Byron PR

    更新日期:2002-03-01 00:00:00

  • Effects of variation in drug elimination on five methods for assessing zero-order drug absorption rates.

    abstract::The area function method for assessing zero-order (ko) drug absorption rates was compared to four other methods under conditions where variation occurs in the plasma concentration data and in the elimination rate constant (kel or k10) for one- or two-compartment models. For deviant kel values of a one-compartment mode...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Cheng HY,Jusko WJ

    更新日期:1990-01-01 00:00:00

  • The pharmacokinetics of trilostane and ketotrilostane in an interconverting system in the rat.

    abstract::The pharmacokinetics of trilostane and one of its metabolites ketotrilostane are described and characterized in the rat following the separate intravenous administration of trilostane and ketotrilostane. It was noted during these studies that the parent compound and its metabolite undergo metabolic interconversion-tri...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: McGee JP,Shaw PN

    更新日期:1992-04-01 00:00:00

  • Improved prediction of in vivo peroral absorption from in vitro intestinal permeability using an internal standard to control for intra- and inter-rat variability.

    abstract:PURPOSE:To evaluate the use of an in vitro intestinal permeability model to predict rat and human absorption as well as to evaluate the use of an internal standard to control for intra- and inter-rat variability. METHODS:In vivo peroral absorption and in vitro steady-state intestinal permeability coefficients were det...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Dowty ME,Dietsch CR

    更新日期:1997-12-01 00:00:00

  • Nonlinear disposition of intravenous 2',3'-dideoxyinosine in rats.

    abstract::The pharmacokinetics of 2',3'-dideoxyinosine (ddI) were examined in rats given intravenous doses of 8, 40, or 200 mg/kg. The concentrations of ddI in whole blood and plasma were identical. The concentration decline was multiexponential, with mean half-lives of 2 and 20 min for the first and second phases, respectively...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Wientjes MG,Mukherji E,Au JL

    更新日期:1992-08-01 00:00:00

  • A Microfluidic Diffusion Cell for Fast and Easy Percutaneous Absorption Assays.

    abstract:PURPOSE:Percutaneous absorption assays of molecules for pharmaceutical and cosmetology purposes are important to determine the bioavailability of new compounds, once topically applied. The current method of choice is to measure the rate of diffusion through excised human skin using a diffusion cell. This method however...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Provin C,Nicolas A,Grégoire S,Fujii T

    更新日期:2015-08-01 00:00:00

  • Experimental and computational screening models for prediction of aqueous drug solubility.

    abstract:PURPOSE:To devise experimental and computational models to predict aqueous drug solubility. METHODS:A simple and reliable modification of the shake flask method to a small-scale format was devised, and the intrinsic solubilities of 17 structurally diverse drugs were determined. The experimental solubility data were us...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Bergström CA,Norinder U,Luthman K,Artursson P

    更新日期:2002-02-01 00:00:00

  • Nanomechanical properties of selected single pharmaceutical crystals as a predictor of their bulk behaviour.

    abstract:PURPOSE:The main goal of this research was to assess the mechanical properties of APIs' polymorphic forms at the single-crystal level (piroxicam, famotidine, nifedipine, olanzapine) in order to predict their bulk deformational attributes, which are critical for some pharmaceutical technology processes. METHODS:The mec...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Egart M,Janković B,Lah N,Ilić I,Srčič S

    更新日期:2015-02-01 00:00:00

  • Heparin-paclitaxel conjugates using mixed anhydride as intermediate: synthesis, influence of polymer structure on drug release, anticoagulant activity and in vitro efficiency.

    abstract:PURPOSE:The heparin-paclitaxel conjugates using amino acid as linker (HD2), with low anticoagulant activity, the similar anticancer activity as paclitaxel, offer great potential for further investigation. METHODS:Two types of heparin-paclitaxel conjugates (HD) have been developed, in which O-acetylated heparin as carr...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Wang Y,Xin D,Liu K,Xiang J

    更新日期:2009-04-01 00:00:00

  • Transport screening of drug cocktails through an in vitro blood-brain barrier: is it a good strategy for increasing the throughput of the discovery pipeline?

    abstract:PURPOSE:The objective of the current study was to investigate whether blood-brain barrier (BBB) permeability studies in vitro could be accelerated by running several compounds together in the same experiment. METHODS:To address this question, we compared the transport of six compounds run separately with the results o...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Berezowski V,Landry C,Lundquist S,Dehouck L,Cecchelli R,Dehouck MP,Fenart L

    更新日期:2004-05-01 00:00:00

  • Blocking effect of an immuno-suppressive agent, cynarin, on CD28 of T-cell receptor.

    abstract:PURPOSE:Cynarin, a potential immunosuppressant that blocks the interaction between the CD28 of T-cell receptor and CD80 of antigen presenting cells, was found in Echinacea purpurea by a new pharmaceutical screening method: After Flowing Through Immobilized Receptor (AFTIR; Dong et al., J Med Chem, 49: 1845-1854, 2006)....

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Dong GC,Chuang PH,Chang KC,Jan PS,Hwang PI,Wu HB,Yi M,Zhou HX,Chen HM

    更新日期:2009-02-01 00:00:00

  • Antiangiogenic activity of orally absorbable heparin derivative in different types of cancer cells.

    abstract:PURPOSE:Orally absorbable anticancer medications have great advantages for conventional cancer therapies to patients. Here we evaluated the potent anticancer effect of orally absorbable LHD, a chemical conjugate of low-molecular-weight heparin and deoxycholic acid, on tumor graft growth models. METHODS:We characterize...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Lee DY,Lee SW,Kim SK,Lee M,Chang HW,Moon HT,Byun Y,Kim SY

    更新日期:2009-12-01 00:00:00

  • Hyaluronic Acid-Based Nanogels Produced by Microfluidics-Facilitated Self-Assembly Improves the Safety Profile of the Cationic Host Defense Peptide Novicidin.

    abstract:PURPOSE:Cationic host defence peptides constitute a promising class of therapeutic drug leads with a wide range of therapeutic applications, including anticancer therapy, immunomodulation, and antimicrobial activity. Although potent and efficacious, systemic toxicity and low chemical stability have hampered their comme...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Water JJ,Kim Y,Maltesen MJ,Franzyk H,Foged C,Nielsen HM

    更新日期:2015-08-01 00:00:00

  • Pulsatile drug release from an insoluble capsule body controlled by an erodible plug.

    abstract:PURPOSE:The objective of this study was to develop and evaluate a pulsatile drug delivery system based on an impermeable capsule body filled with drug and an erodible plug placed in the opening of the capsule body. METHODS:The erodible plugs were either prepared by direct compression followed by placing the tablets in...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Krögel I,Bodmeier R

    更新日期:1998-03-01 00:00:00

  • Hypolipidemic Agents of Phthalimide Derivatives 6. Effects of Aromatic vs. Non-Aromatic Imides.

    abstract::A number of substituted phthalimide, 1, 8-naphthalimide, succinimide and glutarimide derivatives demonstrated significant hypolipidemic activity at 20 mg/kg/ day, I.P. after 16 days dosing. The N-(n-pentyl) succinimide proved to be the most potent analogue of the new compounds, lowering serum triglyceride levels 51 % ...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Chapman JM Jr,Wyrick SD,Maguire JH,Cocolas GH,Hall IH

    更新日期:1984-11-01 00:00:00

  • Effect of cyclodextrins on protein binding of drugs: the diflunisal/hydroxypropyl-beta-cyclodextrin model case.

    abstract::The binding of diflunisal to hydroxypropyl-beta-cyclodextrin (HP beta CD), bovine serum albumin (BSA), human serum albumin (HSA), normal human plasma, and mixed solutions of HP beta CD/protein was studied at 25 degrees C, pH 7.4, by potentiometry using an electrode selective to diflunisal. The experimental data for di...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Sideris EE,Koupparis MA,Macheras PE

    更新日期:1994-01-01 00:00:00

  • Intra- and inter-subject variabilities of CGP 33101 after replicate single oral doses of two 200-mg tablets and 400-mg suspension.

    abstract:PURPOSE:The purpose of this study was to use a replicate designed trial to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters of CGP 33101 after oral administration of tablets relative to that of powder suspended in water, and to determine the relative proportion of the intra-subje...

    journal_title:Pharmaceutical research

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Cheung WK,Kianifard F,Wong A,Mathieu J,Cook T,John V,Redalieu E,Chan K

    更新日期:1995-12-01 00:00:00

  • Initial Drug Dissolution from Amorphous Solid Dispersions Controlled by Polymer Dissolution and Drug-Polymer Interaction.

    abstract:PURPOSE:To identify the key formulation factors controlling the initial drug and polymer dissolution rates from an amorphous solid dispersion (ASD). METHODS:Ketoconazole (KTZ) ASDs using PVP, PVP-VA, HMPC, or HPMC-AS as polymeric matrix were prepared. For each drug-polymer system, two types of formulations with the sa...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Chen Y,Wang S,Wang S,Liu C,Su C,Hageman M,Hussain M,Haskell R,Stefanski K,Qian F

    更新日期:2016-10-01 00:00:00

  • Reversal of signs of induced cotton effects of dicumarol-alpha 1-acid glycoprotein systems by phenothiazine neuroleptics through ternary complexation.

    abstract::The interaction of dicumarol and phenothiazine neuroleptics binding to alpha 1-acid glycoprotein (AGP) was investigated by circular dichroism (CD) and equilibrium dialysis. The induced CD spectra of the dicumarol-AGP complex were affected differently by the different substituents of the phenothiazine molecule. The sig...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Miyoshi T,Yamamichi R,Maruyama T,Otagiri M

    更新日期:1992-07-01 00:00:00

  • Enhanced Cellular Uptake and Gene Silencing Activity of Survivin-siRNA via Ultrasound-Mediated Nanobubbles in Lung Cancer Cells.

    abstract:PURPOSE:Paclitaxel is a first-line drug for the therapy of lung cancer, however, drug resistance is a serious limiting factor, related to overexpression of anti-apoptotic proteins like survivin. To overcome this phenomenon, developing novel ultrasound responsive nanobubbles - nanosized drug delivery system- for the del...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Akbaba H,Erel-Akbaba G,Kotmakçı M,Başpınar Y

    更新日期:2020-08-05 00:00:00

  • Controlled delivery systems for proteins using polyanhydride microspheres.

    abstract::A method to provide near-constant sustained release of high molecular weight, water-soluble proteins from polyanhydride microspheres is described. The polyanhydrides used were poly(fatty acid dimer) (PFAD), poly(sebacic acid) (PSA), and their copolymers [P(FAD-SA)]. P(FAD-SA) microspheres containing proteins of differ...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Tabata Y,Gutta S,Langer R

    更新日期:1993-04-01 00:00:00

  • A spectroscopic investigation of losartan polymorphs.

    abstract::Losartan, an antihypertensive agent in clinical development, was found to exist in two enantiotropic polymorphic forms, a low-temperature stable form (Form I) and a high-temperature stable form (Form II), the temperatures at which they are stable being related to the transition temperature. X-ray powder diffraction pa...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Raghavan K,Dwivedi A,Campbell GC Jr,Johnston E,Levorse D,McCauley J,Hussain M

    更新日期:1993-06-01 00:00:00

  • Recrystallization of nifedipine and felodipine from amorphous molecular level solid dispersions containing poly(vinylpyrrolidone) and sorbed water.

    abstract:PURPOSE:To compare the physical stability of amorphous molecular level solid dispersions of nifedipine and felodipine, in the presence of poly(vinylpyrrolidone) (PVP) and small amounts of moisture. METHODS:Thin amorphous films of nifedipine and felodipine and amorphous molecular level solid dispersions with PVP were s...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Marsac PJ,Konno H,Rumondor AC,Taylor LS

    更新日期:2008-03-01 00:00:00

  • Cyclodextrin-mediated drug release from liposomes dispersed within a bioadhesive gel.

    abstract:PURPOSE:The aim of the present study was to design a new mucosal drug delivery system composed of liposomes dispersed within a bioadhesive hydrogel containing methyl-beta-cyclodextrin (Me(beta)CD) for controlled drug release. METHODS:A hydrophilic model molecule, inulin, was encapsulated within positively charged and ...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Boulmedarat L,Piel G,Bochot A,Lesieur S,Delattre L,Fattal E

    更新日期:2005-06-01 00:00:00

  • In Vivo performance of ophthalmic preparations of betamethasone and phenylephrine hydrochloride in the rabbit eye: Effect of polyvinyl alcohol.

    abstract::The effect of different concentrations of polyvinyl alcohol 14000 and 72000 (PVA 14 and 72) on the activity of betamethasone and phenylephrine hydrochloride in the rabbit eye was investigated. The polymer of higher molecular weight exerts a more pronounced effect at relatively lower viscosities. Effects on the intraoc...

    journal_title:Pharmaceutical research

    pub_type: 杂志文章


    authors: Kassem MA,Attia MA,Habib FS,Mohamed AR

    更新日期:1986-08-01 00:00:00