Soluble Polymers as Targetable Drug Carriers

Krinick, Nancy L.; Kopeček, Jindřich

doi:10.1007/978-3-642-75862-1_5

Cited by 21 publications

(20 citation statements)

References 180 publications

(138 reference statements)

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“…Oligopeptidyl spacers were the most thoroughly studied. 2,19,27,28 It was found that this type of spacer can be designed to have a structure that remains stable during transport and releases the drug in its active form intracellularly by matching the specificities of certain lysosomal enzymes. 42 However, in this study, we found that the attachment of the oligopeptides linking the bioactive compounds to the polymeric carriers decreases the probability of backbone cleavage.…”

Section: Discussionmentioning

confidence: 99%

“…19 In addition, the permeability limit of the lysosomal membrane lies approximately at the size of dipeptides 20 and, subsequently, may further restrict the usefulness of the polymeric drug carriers to anticancer chemotherapy. 2,19 Although poly(␣-amino acids) have been considered enzymatically degradable, the relationship between their lysosomal degradability and their structure was not systematically studied. In this study, poly(L-glutamic acid) and its derivatives/copolymers were selected and their lysosomal degradability evaluated.…”

Section: Discussionmentioning

confidence: 99%

“…20 The degradation products of macromolecular carriers by lyso-somal enzymes after endocytosis may be too large to diffuse out of the lysosomal compartment. 19,21 Conjugation of polymeric carriers with bioactive agents including targeting moieties may further change their degradation pattern and consequently their clinical usefulness.…”

Section: Introductionmentioning

confidence: 99%

“…17,18 In addition, the enzymatic degradability of macromolecules as lysosomotropic drug carriers can strongly influence their biocompatibility due to the fact that the long-term residences of polymeric carriers in the body may produce adverse effects. 2,19 Consequently, the structure of the carriers should be designed to be eliminated from the body after fulfilling their biological function. Foster and Lloyd pointed out that the permeability limit of lysosomal membranes lies approximately at the size of dipeptides.…”

Section: Introductionmentioning

confidence: 99%

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Lysosomal degradability of poly(?-amino acids)

Chiu

Kopečková

Deshmane

et al. 1997

J. Biomed. Mater. Res.

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The lysosomal degradability of poly(alpha-amino acids) based on poly(L-glutamic acid) and its derivatives/copolymers was evaluated to gain insight into the subcellular fate of the macromolecules as water soluble polymeric drug carriers. The results indicate that both the incorporation of hydrophobic comonomers and modification of the carboxylic groups of glutamic acid side chains with hydroxyalkylamine increase the lysosomal degradability of the copolymers. Decreased lysosomal degradability of L-glutamic acid copolymers containing tripeptides terminated in p-nitroanilide (drug model) in the side chains confirmed that drug conjugation alters the degradation pattern of the polymeric carriers. The percentages of the enzymatic release of p-nitroaniline from its polymeric complex with time is relatively independent of the contents of the tripeptidyl p-nitroanilides attached to the polymeric conjugates. Determination of the degradation products by electrospray mass spectroscopy showed that no fragments less than 10(3) D were generated by lysosomal enzymes, whereas the main degradation products by papain and chymotrypsin were tripeptides and tetrapeptides. The conclusions derived from these data strongly suggest that these macromolecules, if used as lysosomotropic drug carriers, may accumulate in the lysosomes and limit their usefulness in some applications.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lysosomal degradability of poly(?-amino acids)

Chiu

Kopečková

Deshmane

et al. 1997

J. Biomed. Mater. Res.

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“…Renal filtration and endocytosis are two major processes that affect the distribution of water-soluble polymers in the body (30). The main interrelated factors influencing the distribution volumes in the body and the rate of elimination of a macromolecular carrier from the body include its chemical structure, molecular size [weight and chemical conformation), and biodegradability.…”

Section: Discussionmentioning

confidence: 99%

Effect of varying the molecular weight of the MR contrast agent Gd‐DTPA‐polylysine on blood pharmacokinetics and enhancement patterns

Vexler¹,

Clémеnt²,

Schmitt‐Willich³

et al. 1994

Magnetic Resonance Imaging

102

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The effects of varying the molecular weight of gadolinium-DTPA (diethylenetriaminepentaacetic acid)-polylysine, a macromolecular magnetic resonance (MR) imaging contrast agent, on blood pharmacokinetics and dynamic tissue MR imaging signal enhancement characteristics were studied in normal rats. Blood elimination half-life, total blood clearance, volume of the central compartment (Vcc) and the steady-state distribution volume (Vssd) were calculated for four Gd-DTPA-polylysine polymers with average molecular weights of 36, 43.9, 139, and 480 kd and compared with corresponding values for Gd-DTPA (0.57 kd) and Gd-DTPA-albumin (92 kd). Blood elimination half-life increased seven-fold with an increase in molecular weight from 36 to 480 kd. The Vcc values for all polylysine polymers did not differ significantly from the Vcc value for Gd-DTPA-albumin but were significantly smaller than the Vcc value for Gd-DTPA. The Vssd value for Gd-DTPA did not differ significantly from the Vssd value for the 36- and 43.9-kd polymers but was significantly larger than the Vssd values for the 139- and 480-kd polymers and for Gd-DTPA-albumin. On T1-weighted coronal spin-echo MR images, dynamic signal enhancement profiles in liver and kidney for the 36-, 43.9-, and 480-kd Gd-DTPA-polylysine chelates corresponded to the blood pharmacokinetic data. Increasing molecular weight of Gd-DTPA-polylysine formulations substantially slows blood clearance and produces a prolonged, almost constant tissue signal enhancement for the 60-minute observation period.

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Design of Polymer‐Drug Conjugates

Kopeček

Kopečková

2011

Drug Delivery in Oncology

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Soluble Polymers as Targetable Drug Carriers

Cited by 21 publications

References 180 publications

Lysosomal degradability of poly(?-amino acids)

Lysosomal degradability of poly(?-amino acids)

Effect of varying the molecular weight of the MR contrast agent Gd‐DTPA‐polylysine on blood pharmacokinetics and enhancement patterns

Design of Polymer‐Drug Conjugates

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