Polymer-drug conjugates: manipulating drug delivery kinetics using model LCST systems

Shah, S.S.; Wertheim, Jason A.; Wang, C T; Pitt, Colin G.

doi:10.1016/s0168-3659(96)01550-7

Cited by 35 publications

(15 citation statements)

References 14 publications

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“…The physicochemical properties of the polymer then become critical and need to be engineered to control the protein delivery kinetics. In addition to controlled delivery (Bromberg and Ron, 1998;Kwonand and Okano, 1999;Shah et al, 1997), the thermoreversible polymers have found applications for delivery of anti-thrombogenic agents on blood-contacting surface (Gutowska et al, 1995), transplantation of mammalian cells (Shimizu et al, 1996;Stile et al, 1999), and enzyme immobilization (Ding et al, 1998;Matsukata et al, 1996;Korenbrodt et al 1987).…”

Section: Introductionmentioning

confidence: 99%

Engineering temperature‐sensitive poly(N‐isopropylacrylamide) polymers as carriers of therapeutic proteins

Uludağ

Norrie

Kousinioris

et al. 2001

Biotech & Bioengineering

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This study was carried out to engineer N-isopropylacrylamide (NiPAM) polymers that contain protein-reactive N-acryloxysuccinimide (NASI) and hydrophobic alkylmethacrylates (AMAs). These thermoreversible, protein-conjugating polymers hold potential for retention of therapeutic proteins at an application site where tissue regeneration is desired. The lower critical solution temperatures (LCST) of the polymers were effectively controlled by the AMA mole content. The AMAs with longer side-chains were more effective in lowering the LCST. Polymers without NASI exhibited a stable LCST in phosphate buffer and in serum over a 10-day study period. The LCST of polymers containing NASI was found to increase over time in phosphate buffer, but not in serum-containing medium. The LCST increase in phosphate buffer was proportional to the AMA content. The feasibility of localizing a therapeutic protein, recombinant human bone morphogenetic protein-2 (rhBMP-2), to a site of application was explored in a rat intramuscular injection model. The results indicated that polymers capable of conjugating to rhBMP-2 were most effective in localizing the protein irrespective of the LCST (13-25 degrees C). For polymers with no NASI groups, a lower LCST resulted in a better rhBMP-2 localization. We conclude that thermosensitive polymers can be engineered for delivery of therapeutic proteins to improve their therapeutic efficacy.

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Section: Introductionmentioning

confidence: 99%

Engineering temperature‐sensitive poly(N‐isopropylacrylamide) polymers as carriers of therapeutic proteins

Uludağ

Norrie

Kousinioris

et al. 2001

Biotech & Bioengineering

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“…Such a strategy was reported by Shah et al 58 using N-hydroxysuccinimide as a model drug in the polymer-drug conjugate poly(-NIPAAm-co-N-acryloxysuccinimide). These materials have the advantage of releasing drug in concert with the rate of degradation of the bond linking the drug to the polymer backbone, and degradation leaves an acid group on the polymer backbone, raising the LCST and allowing for dissolution of the polymer.…”

Section: N-isopropylacrylamide-based Hydrogelsmentioning

confidence: 97%

Injectable hydrogels

Overstreet

Dutta

Stabenfeldt

et al. 2012

J Polym Sci B Polym Phys

159

124

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Hydrogels are promising for a variety of medical applications due to their high water content and mechanical similarity to natural tissues. When made injectable, hydrogels can reduce the invasiveness of application, which in turn reduces surgical and recovery costs. Key schemes used to make hydrogels injectable include in situ formation due to physical and/or chemical cross-linking. Advances in polymer science have provided new injectable hydrogels for applications in drug delivery and tissue engineering. A number of these injectable hydrogel systems have reached the clinic and impact the health care of many patients. However, a significant remaining challenge is translating the ever-growing family of injectable hydrogels developed in laboratories around the world to the clinic. V C 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 50: 2012

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“…Thermoresponsive terpolymer of N-isopropylmethacrylamide, N-propylmethacrylamide and N-methacryloyl glycylglycinehydrazide with acid sensitive hydrazone bond has also been used as degradable carrier for conjugation [69]. Polylysine, a poly(amino acid) and Poly(2-acrylamido-2-(hydroxyl methyl)propane-1,3-diol have been used for delivery of daunomycin and daunorubucin respectively [24].…”

Section: Miscellaneousmentioning

confidence: 99%

Exploiting EPR in Polymer Drug Conjugate Delivery for Tumor Targeting

Modi¹,

Jain²,

Domb³

et al. 2006

CPD

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Treatment of tumor tissue without affecting normal cells has always been formidable task for drug delivery scientists and this task is effectively executed by polymer drug conjugate (PDC) delivery. The novelty of this concept lies in the utilization of a physical mechanism called enhanced permeability and retention (EPR) for targeting tumors. EPR is a physiological phenomenon that is customary for fast growing tumor and solves the problem of targeting the miscreant tissue. PDCs offer added advantages of reduced deleterious effects of anticancer drugs and augmentation of its formulation capability (e.g. Solubility). There are now at least eleven PDCs that have entered phase I/II/III clinical trial as anticancer drugs. PDCs once entered into the tumor tissue, taking advantage of EPR, are endocytosed into the cell either by simple or receptor mediated endocytosis. Various polymeric carriers have been used with hydrolyzable linker arm for conjugation with bioactive moiety. The hydrolyzable linkages of PDC are broken down by acid hydrolyses of lysosomes and releases the drug. High concentrations of the chemotherapeutic agent are maintained near the nucleus, the target site. Passive targeting by PDCs is due to the physiological event of EPR, which is becoming one of the major thrust areas for targeting solid tumors.

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Polymer-drug conjugates: manipulating drug delivery kinetics using model LCST systems

Cited by 35 publications

References 14 publications

Engineering temperature‐sensitive poly(N‐isopropylacrylamide) polymers as carriers of therapeutic proteins

Engineering temperature‐sensitive poly(N‐isopropylacrylamide) polymers as carriers of therapeutic proteins

Injectable hydrogels

Exploiting EPR in Polymer Drug Conjugate Delivery for Tumor Targeting

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