Dextran Retention in the Rat Brain Following Release from a Polymer Implant

Dang, Wenbin; Saltzman, W. Mark

doi:10.1021/bp00018a009

Cited by 24 publications

(10 citation statements)

References 23 publications

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“…For CPT, this experimentally determined diffusion coefficient (0.282 mm 2 /h) was significantly lower than what we empirically calculated (0.825 mm 2 /h) both from Wilke-Chang and from molecules of comparable molecular weights (15). Lower-thanexpected experimental diffusion coefficients have been reported for other small molecules such as paclitaxel (16) and fluorescein (10). Experimental PEG3400 conjugate diffusion coefficients (0.14 mm 2 /h) in rat brains, assuming an elimination rate of 1.5 × 10 -5 s -1 , were also found to be lower than expected for PEG based on Wilke-Chang and aqueous experimental values (17) (0.18 mm 2 /h) for equivalent PEG molecular weight.…”

Section: Methodsmentioning

confidence: 76%

Conjugation to Increase Treatment Volume during Local Therapy: A Case Study with PEGylated Camptothecin

2007

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Controlled release of chemotherapy drugs from polymer implants placed directly at the tumor site is a proven method for treatment of cancers of the brain. Although this method provides high doses of drug at the tumor site, the drug does not penetrate far enough into the brain for optimum treatment in most cases. Rapid drug elimination leads to more than a 10-fold drop in concentration within 2 mm of the implant. Conjugation to water-soluble polymers, such as poly(ethylene glycol) (PEG) or dextran, has the potential to increase drug distribution in the brain. We have recently PEGylated the chemotherapy drug camptothecin and found a large increase in the extent of distribution of camptothecin in the rat brain, but most of the drug in tissue was in the less-active conjugated form. Stability of the conjugation bond, activity of the drug-polymer conjugate, solubility of the conjugate relative to the drug, and molecular weight of the polymer must all be considered in the design of a conjugate to maximize drug distribution. Therefore, to optimize the PEGylated system, we have developed a pharmacokinetic model to determine the relative importance of parameters involved in the distribution of drug-polymer conjugates after release from a polymer implant. Our modeling shows that PEGylation has the potential to increase treatment distances to more than a centimeter, which may be sufficient to prevent the recurrence of human brain tumors.

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Section: Methodsmentioning

confidence: 76%

Conjugation to Increase Treatment Volume during Local Therapy: A Case Study with PEGylated Camptothecin

2007

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“…Absorbance was measured at 595 nm using the microplate reader, and protein concentration was determined by comparison with a standard curve. Implantation ofpo(vmei"3. into rat br-ains Polymers containing mNGF and BSA, mNGF and carboxymethyldextran, mNGF-dextran conjugate and dextran, and rhNGF and BSA were implanted into the brains of 6-7 week old male Fisher 344 rats for up to I week according to previously published procedures [ 14,20]. Polymers containing only the codispersant (no NGF) were implanted into control rats.…”

Section: Controlled Release Of Proteins Into Pbsmentioning

confidence: 99%

“…The effect of the codispersant species on the stability of NGF within the polymer and release of NGF from the device was examined in non-degradable poly-(ethylene-co-vinyl acetate) (EVAc) matrices and degradable poly(lactic acid) (PLA) microspheres. To improve penetration of NGF within brain tissue, NGF was also conjugated to dextran, a molecule which has greater penetrating ability than NGF in brain interstitium [12,20]. Our results indicate that the rate of release of NGF from a polymer matrix into buffered water can be modulated by changes in the formulation of the polymer, but that these changes have a minor influence on NGF concentration in the brain following delivery.…”

Section: Introductionmentioning

confidence: 99%

Stabilization of nerve growth factor in controlled release polymers and in tissue

Krewson

Dause

Mak

et al. 1997

Journal of Biomaterials Science, Polymer Edition

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We have studied the release of nerve growth factor (NGF), a protein under consideration for treatment of Alzheimer's Disease, from polymer matrices and microspheres to characterize the stability of NGF, the dynamics of NGF release, and the distribution of NGF within the brain interstitium. Poly(ethylene-co-vinyl acetate) (EVAc) disks and poly(L-lactic acid) (PLA) microspheres were formed by codispersing NGF with one of a variety of molecules. The mass of mouse NGF (mNGF) detected following release from EVAc disks into buffered saline varied five-fold over the range of codispersants studied, with carboxymethyldextran providing optimal release, while the mass of recombinant human NGF (rhNGF) released varied four-fold from both EVAc disks and PLA microspheres, with albumin and carboxymethyldextran providing optimal release. Variation of the codispersant species significantly affected NGF release into buffered saline; it also had a noticeable, but small, effect of the amount of NGF found in the brain tissue following implantation of a polymer device. To improve NGF retention in tissue, NGF was conjugated to 70 000 molecular weight dextran and incorporated into a polymeric device. The distribution of NGF was enhanced by conjugation; comparison of NGF concentrations in the brain to a mathematical model of diffusion and elimination suggested that the elimination rate of NGF-dextran conjugate in the tissue was over seven times slower than the elimination rate of NGF. These results indicate that variation of the properties of the controlled release system may be useful in regulating the time course of NGF delivery to tissue, and that modification of the NGF itself can improve penetration and retention in the brain.

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“…Langer, Göpferich and others have extensively evaluated degradation in polyanhydrides due to the hydrolytic lability of the anhydride bond 10, 18–32 as the highly hydrophobic nature of these polymers makes them ideal candidates for drug delivery applications. 24, 31–51 The hydrophobicity prohibits water from effectively permeating the polymer matrix so that the rate of hydrolysis is faster than the rate of water diffusion into the matrix. A direct consequence of this phenomenon is that these polymers predominantly undergo surface erosion.…”

Section: Introductionmentioning

confidence: 99%

Poly(anhydride‐ester) fibers: Role of copolymer composition on hydrolytic degradation and mechanical properties

Whitaker-Brothers

Uhrich

2004

J Biomedical Materials Res

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Poly(anhydride-esters), based on carboxyphenoxydecanoate (CPD), are biocompatible polymers that hydrolytically degrade. The mechanical properties of the poly(anhydride-esters) can be altered by copolymerization with para-carboxyphenoxyhexane (pCPH). Mechanical properties of three CPD:pCPH compositions (30:70, 40:60, and 50:50) are reported as a function of hydrolytic degradation. The mechanical characteristics evaluated were tensile modulus at 1% strain (E(1%)), tensile strength (sigma(B)), ultimate elongation (epsilon(B)), and toughness (E(r)). The 30:70 CPD:pCPH fibers maintained higher values for tensile modulus at all time points than the two other fiber compositions. In addition, the 30:70 CPD:pCPH fibers maintained lower values for both tensile strength and toughness than the two other fiber compositions. These phenomena resulted from the brittle nature of pCPH, the major component of the 30:70 CPD:pCPH fibers; increasing the pCPH concentration in the polymer lowers both tensile strength and toughness of the polymer by decreasing ductility. With increasing amounts of pCPH, the hydrolytic degradation occurred more slowly, as reflected in the copolymers' improved ability to retain their mechanical properties. Therefore, copolymerization is useful for controlling the mechanical properties of the fibers as well as the polymer degradation rate, which ultimately determines the rate at which physically or chemically encapsulated drugs can be released.

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Dextran Retention in the Rat Brain Following Release from a Polymer Implant

Cited by 24 publications

References 23 publications

Conjugation to Increase Treatment Volume during Local Therapy: A Case Study with PEGylated Camptothecin

Conjugation to Increase Treatment Volume during Local Therapy: A Case Study with PEGylated Camptothecin

Stabilization of nerve growth factor in controlled release polymers and in tissue

Poly(anhydride‐ester) fibers: Role of copolymer composition on hydrolytic degradation and mechanical properties

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