Evaluation of protein-N-(2-hydroxypropyl)methacrylamide copolymer conjugates as targetable drug carriers. 1. Binding, pinocytic uptake and intracellular distribution of transferrin and anti-transferrin receptor antibody conjugates

Flanagan, Pauline A.; Kopečková, Pavla; Kopeček, Jindřich; Duncan, Ruth

doi:10.1016/0304-4165(89)90146-3

Cited by 36 publications

(9 citation statements)

References 29 publications

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“…The concept of targeted protein delivery using polymers [39] and PNC dates to at least early 1980s [40], yet advance in this area is relatively modest and slow compared to that of PNC delivery of small therapeutics like doxorubicin [41,42] and oligo-nucleic acids [43]. The primary stumbling block has been that the available formulation methods (e.g., phase separation, micellization and mechanical or ultrasound homogenization) typically result in low loading levels and/or protein inactivation.…”

Section: Discussionmentioning

confidence: 99%

Endothelial targeting of semi-permeable polymer nanocarriers for enzyme therapies

et al. 2008

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The medical utility of proteins, e.g. therapeutic enzymes, is greatly restricted by their labile nature and inadequate delivery. Most therapeutic enzymes do not accumulate in their targets and are inactivated by proteases. Targeting of enzymes encapsulated into substrate-permeable polymer nano-carriers (PNC) impermeable for proteases might overcome these limitations. To test this hypothesis, we designed endothelial targeted PNC loaded with catalase, an H(2)O(2)-detoxifying enzyme, and tested if this approach protects against vascular oxidative stress, a pathological process implicated in ischemia-reperfusion and other disease conditions. Encapsulation of catalase (MW 247 kD), peroxidase (MW 42 kD) and xanthine oxidase (XO, MW 300 kD) into approximately 300 nm diameter PNC composed of co-polymers of polyethylene glycol and poly-lactic/poly-glycolic acid (PEG-PLGA) was in the range approximately 10% for all enzymes. PNC/catalase and PNC/peroxidase were protected from external proteolysis and exerted enzymatic activity on their PNC diffusible substrates, H(2)O(2) and ortho-phenylendiamine, whereas activity of encapsulated XO was negligible due to polymer impermeability to the substrate. PNC targeted to platelet-endothelial cell (EC) adhesion molecule-1 delivered active encapsulated catalase to ECs and protected the endothelium against oxidative stress in cell culture and animal studies. Vascular targeting of PNC-loaded detoxifying enzymes may find wide medical applications including management of oxidative stress and other toxicities.

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Section: Discussionmentioning

confidence: 99%

Endothelial targeting of semi-permeable polymer nanocarriers for enzyme therapies

et al. 2008

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“…Simple monosaccharide or oligopeptide targeting moieties as well as more complex polyclonal and monoclonal antibodies (Ab) or Ab fragments targeting T-lymphocytes, 297 transferrin receptor, 298 or human colorectal carcinoma 299 were attached to carriers using an aminolysis reaction in which reactive ester groups on a polymer precursor were aminolyzed by primary amino groups on the ligands. One of these Ab-targeted conjugates, a conjugate of P(HPMA) with the photosensitizer chlorin e 6 (mesochlorin), was used to assess the concept of double-targeted anticancer agents.…”

Section: Chemical Reviewsmentioning

confidence: 99%

Targeted Drug Delivery with Polymers and Magnetic Nanoparticles: Covalent and Noncovalent Approaches, Release Control, and Clinical Studies

et al. 2016

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Targeted delivery combined with controlled drug release has a pivotal role in the future of personalized medicine. This review covers the principles, advantages, and drawbacks of passive and active targeting based on various polymer and magnetic iron oxide nanoparticle carriers with drug attached by both covalent and noncovalent pathways. Attention is devoted to the tailored conjugation of targeting ligands (e.g., enzymes, antibodies, peptides) to drug carrier systems. Similarly, the approaches toward controlled drug release are discussed. Various polymer-drug conjugates based, for example, on polyethylene glycol (PEG), N-(2-hydroxypropyl)methacrylamide (HPMA), polymeric micelles, and nanoparticle carriers are explored with respect to absorption, distribution, metabolism, and excretion (ADME scheme) of administrated drug. Design and structure of superparamagnetic iron oxide nanoparticles (SPION) and condensed magnetic clusters are classified according to the mechanism of noncovalent drug loading involving hydrophobic and electrostatic interactions, coordination chemistry, and encapsulation in porous materials. Principles of covalent conjugation of drugs with SPIONs including thermo- and pH-degradable bonds, amide linkage, redox-cleavable bonds, and enzymatically-cleavable bonds are also thoroughly described. Finally, results of clinical trials obtained with polymeric and magnetic carriers are analyzed highlighting the potential advantages and future directions in targeted anticancer therapy.

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“…The homopolymer of N-(2-hydroxypropyl)methacrylamide (HPMA) and its copolymers have been extensively studied as carriers for the site-specific and targeted delivery of drugs [185][186][187][188][189][190]. It was shown that HPMAbased polymers exhibit little immunogenicity [191,192], and they are both pinocytosed by cells [193,194] and distributed in organs or excreted [195] in a molecularweight-dependent manner.…”

Section: Copolymers Of N-(2-hydroxypropyl) Methacrylamidementioning

confidence: 99%

The use of synthetic polymers for delivery of therapeutic antisense oligodeoxynucleotides

et al. 2002

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Developed over the past two decades, the antisense strategy has become a technology of recognised therapeutic potential, and many of the problems raised earlier in its application have been solved to varying extents. However, the adequate delivery of antisense oligodeoxynucleotides to individual cells remains an important and inordinately difficult challenge. Synthetic polymers appeared on this scene in the middle 1980s, and there is a surprisingly large variety used or proposed so far as agents for delivery of oligodeoxynucleotides. After discussing the principles of antisense strategy, certain aspects of the ingestion of macromolecules by cells, and the present situation of delivery procedures, this article analyses in detail the attempts to use synthetic polymers as carrier matrices and or cell membrane permeabilisation agents for delivery of antisense oligodeoxynucleotides. Structural aspects of various polymers, as well as the results, promises and limitations of their use are critically evaluated.

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Evaluation of protein-N-(2-hydroxypropyl)methacrylamide copolymer conjugates as targetable drug carriers. 1. Binding, pinocytic uptake and intracellular distribution of transferrin and anti-transferrin receptor antibody conjugates

Cited by 36 publications

References 29 publications

Endothelial targeting of semi-permeable polymer nanocarriers for enzyme therapies

Endothelial targeting of semi-permeable polymer nanocarriers for enzyme therapies

Targeted Drug Delivery with Polymers and Magnetic Nanoparticles: Covalent and Noncovalent Approaches, Release Control, and Clinical Studies

The use of synthetic polymers for delivery of therapeutic antisense oligodeoxynucleotides

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