Polyanhydrides as localized drug delivery carrier: an update

Jain, Jay Prakash; Chitkara, Deepak; Kumar, Neeraj

doi:10.1517/17425247.5.8.889

Cited by 55 publications

(30 citation statements)

References 107 publications

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“…Gliadel® and Septacin™ are the traditional examples of clinical drug delivery systems using modified polyanhydrides. 33 Gliadel wafers are comprised of 1,3-bis-(p-carboxyphenoxy) propane-co-sebacic acid In short, in most of above mentioned material-based systems (both surface eroding and bulk eroding systems), the solute was released after fixed period of time either by dissolution, degradation or rupture by osmotic pressure. While it is possible to produce multiple pulses using such mechanism by protecting the solute in number of shells with variable expiration time, the independent nature of each set of shells filled with solute limits the number of pulses that can be delivered.…”

Section: Surface Eroding Systemsmentioning

confidence: 99%

Barrier-Mediated Pulsatile Release

Gandhi

Gosse

Nishii

et al. 2015

Journal of Membrane Science

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ii To my loving wife and wonderful parents.iii ACKNOWLEDGMENTS First and foremost I would like to thank my research advisor Dr. Eric Nuxoll for his support, brilliant advice, professionalism and endless patience. He has been a great mentor throughout my doctoral studies at the University of Iowa since I became his first graduate student. Besides overall research skills, I learned much more including how to address a problem in a practical way, determine priorities and most importantly how to express and defend ideas. I have had the privilege to work with very talented undergrad students Matthew Gosse and Derek Baerenwald, who directly contributed to this project. I am also grateful to Yasuhiro Nishii, a visiting scholar from Japan, for his partial contributions to this work and continued work forward with this project. Guiding and mentoring these bright individuals was an exciting opportunity and also a great experience for me. Others who have helped me along the way include my fellow research group members Ann O'Toole, Joel Coffel, Erica Bader and Bryce Hundley. iv I am incredibly grateful to my parents who have always supported me. I have been blessed to be born in a loving family that has fully encouraged and enabled me to achieve my dreams. Finally, no words can express my thankfulness to Khushbu, my wife, who always stood by me throughout this journey. Without her encouragement and motivation I would not have pursued the education to the length I have.v ABSTRACT Solutes are often most efficiently deployed in discrete pulses, for example in the delivery of herbicides or drugs. Manual application of each pulse can be labor-intensive, automated application of each pulse can be capital intensive, and both are often costly and impractical. Barrier-Mediated Pulsatile Release (BMPR) systems offer a materialsbased alternative for automated pulsatile drug delivery, without pumps, power supplies, or complex circuitry. While earlier materials-based approaches such as delayed-release microcapsules are limited to two or three pulses due to the independent nature of each pulse's timing control, BMPR systems link the timing of each pulse to the previous pulse.Each dose of drug is sequestered in its own stimuli-sensitive depot, releasing only upon contact with the stimulant. These depots are stacked with sacrificial barriers in between, each of which block the stimulant for a predetermined time. For instance, layers of soluble drug may be separated by degradable polymer layers. Water, as the stimulant, will erode the polymer layer over a fixed period of time, followed by quick dissolution and release of the underlying drug and the start of degradation for the next polymer layer.This example, however, is quickly limited by irregular polymer erosion, a single stimulant (water), and difficulty in scaling delay times.The research work presented in this thesis reports the development of a generalized BMPR system which overcomes those limitations. Model drugs (methylene blue and methyl orange) were immobilized in a pH-sensitive ...

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Section: Surface Eroding Systemsmentioning

confidence: 99%

Barrier-Mediated Pulsatile Release

Gandhi

Gosse

Nishii

et al. 2015

Journal of Membrane Science

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“…Drug release may be driven either by diffusion of the drug from the polymeric depot, cleavage of the chemical bond between polymeric carrier and the drug, degradation of the polymeric implant, or by combination of these mechanisms [6][7][8] . Besides, controlled chemical degradation of the implant forming polymer (desirable for many in vivo applications) may proceed in whole volume, e.g., hydrazone based hydrogels 9 , from the surface only, e.g., polyanhydrides [10][11][12] , or by combination of both, e.g., polylactides 8,13 .…”

Section: Introductionmentioning

confidence: 99%

“…Polyanhydrides such as poly(sebacic acid) are relatively hydrophobic polymers that degrade in aqueous milieu, by hydrolysis of carboxylic acid anhydride bond into low molecular weight water-soluble dicarboxylic acids which are further metabolized or excreted 10,11,13 . Since, hydrolysis of polyanhydrides strictly begin at the surface so the inner volume of the implant remains dry, until the hydrolytic zone on the surface reaches completely to the core.…”

Section: Introductionmentioning

confidence: 99%

“…Since, hydrolysis of polyanhydrides strictly begin at the surface so the inner volume of the implant remains dry, until the hydrolytic zone on the surface reaches completely to the core. Rate of hydrolysis is inversely proportional to the hydrophobicity of the monomer (increased hydrophobicity decreases degradation rate), and can be controlled upon modification with highly hydrophobic fatty acids 14 , or with use of monomeric composition that increases crystallinity, such as conformationally rigid cyclic diacid comonomers (eg., 1,4-cyclohexanedicarboxylic acid), or aromatic diacid monomers [10][11][12] . This study describes a conceptually new system exploiting the ability of the polyanhydrides to hydrolyze from the surface only, to release the hydrolytically labile drugs, AZA and DAC.…”

Section: Introductionmentioning

confidence: 99%

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Biodegradable system for drug delivery of hydrolytically labile azanucleoside drugs

Hrubý¹,

Agrawal²,

Policianova³

et al. 2016

BIOMED PAP

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Background. The archetypal DNA methyltransferase inhibitors, 5-azacytidine (AZA) and 5-aza-2'-deoxycytidine (DAC) are potent antineoplastic agents used in the treatment of mainly, blood malignancies. However, the administration of these drugs is confounded by their hydrolytic lability which decreases plasma circulation time. Here, we describe a new biodegradable, polyanhydride formulation for drug delivery that circumvents this drawback. Methods. Injectable/implantable polymeric microbeads containing dispersed microcrystals of hydrophilic AZA or DAC packed in a dry environment are protected from hydrolysis, until the hydrolytic zone reaches the core. Diclofenac is embedded into the formulation to decrease any local inflammation. The efficacy of the formulations was confirmed by monitoring the induced demethylation, and cytostatic/cytotoxic effects of continuous drug release from the timecourse dissolution of the microbeads, using an in vitro developed cell based reporter system. Results. Poly(sebaccic acid-co-1,4-cyclohexanedicarboxylic acid) containing 30 wt. % drug showed zero-order release (R 2 = 0.984 for linear regression), and release rate of 10.0 %/h within the first 5 h, and subsequent slower release of the remaining drug, thus maintaining the level of drugs in the outer environment considerably longer than the typical plasma half-life of free azanucleosides. At lower concentrations, the differences between powder drug formulations and microbeads were very low or negligible, however, at higher concentrations, we discovered equivalent or increasing effects of the drugs loaded in microbeads. Conclusions. The study provides evidence that microbead formulations of the hydrolytically labile azanucleoside drugs could prevent their chemical decomposition in aqueous solution, and effectively increase plasma circulation time.

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AbstractNanoparticulate systems have emerged as valuable tools in vaccine delivery through their ability to efficiently deliver cargo, including proteins, to antigen presenting cells [1][2][3][4][5] . Internalization of nanoparticles (NP) by antigen presenting cells is a critical step in generating an effective immune response to the encapsulated antigen.

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mentioning

confidence: 99%

Analyzing Cellular Internalization of Nanoparticles and Bacteria by Multi-spectral Imaging Flow Cytometry

Phanse

Ramer‐Tait

Friend

et al. 2012

JoVE

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Nanoparticulate systems have emerged as valuable tools in vaccine delivery through their ability to efficiently deliver cargo, including proteins, to antigen presenting cells [1][2][3][4][5] . Internalization of nanoparticles (NP) by antigen presenting cells is a critical step in generating an effective immune response to the encapsulated antigen. To determine how changes in nanoparticle formulation impact function, we sought to develop a high throughput, quantitative experimental protocol that was compatible with detecting internalized nanoparticles as well as bacteria. To date, two independent techniques, microscopy and flow cytometry, have been the methods used to study the phagocytosis of nanoparticles. The high throughput nature of flow cytometry generates robust statistical data. However, due to low resolution, it fails to accurately quantify internalized versus cell bound nanoparticles. Microscopy generates images with high spatial resolution; however, it is time consuming and involves small sample sizes 6-8 . Multi-spectral imaging flow cytometry (MIFC) is a new technology that incorporates aspects of both microscopy and flow cytometry that performs multi-color spectral fluorescence and bright field imaging simultaneously through a laminar core. This capability provides an accurate analysis of fluorescent signal intensities and spatial relationships between different structures and cellular features at high speed.Herein, we describe a method utilizing MIFC to characterize the cell populations that have internalized polyanhydride nanoparticles or Salmonella enterica serovar Typhimurium. We also describe the preparation of nanoparticle suspensions, cell labeling, acquisition on an ImageStream X system and analysis of the data using the IDEAS application. We also demonstrate the application of a technique that can be used to differentiate the internalization pathways for nanoparticles and bacteria by using cytochalasin-D as an inhibitor of actin-mediated phagocytosis. Video LinkThe video component of this article can be found at http://www.jove.com/video/3884/ Protocol 1. RAW 264.7 Cell Culture 1. Harvest RAW 264.7 cells from their flasks when they reach confluency by scraping them gently with a cell scraper. Count and plate them into a 24-well cell culture dish at a density of 5 x 10 5 cells/well in 0.5 mL complete Dulbecco's Modified Eagle Medium (cDMEM; 10% heat-inactivated fetal bovine serum (FBS), 2 mM Glutamax, and 10 mM HEPES) and incubate overnight at 37°C in a 5% CO2 incubator. Pathogenic Salmonella enterica Serovar Typhimurium 14028 Transformation and Culture1. Introduce recombinant plasmids expressing green fluorescent protein (GFP) to S. Typhimurium by electroporation. First, prepare culture of Salmonella enterica serovar Typhimurium (ATCC 14028) in LB broth and incubate overnight at 37°C with aeration. 2. Next day, pellet 1 mL of bacteria at maximum speed in a microcentrifuge. Wash the cells four times with 1 mL of cold MOPS/glycerol solution (1 mM 3-(N-morpholino)propanesulfonic acid (...

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Polyanhydrides as localized drug delivery carrier: an update

Cited by 55 publications

References 107 publications

Barrier-Mediated Pulsatile Release

Barrier-Mediated Pulsatile Release

Biodegradable system for drug delivery of hydrolytically labile azanucleoside drugs

Analyzing Cellular Internalization of Nanoparticles and Bacteria by Multi-spectral Imaging Flow Cytometry

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