A Polyethylene Glycol Copolymer for Carrying and Releasing Multiple Copies of Cysteine-Containing Peptides

Huang, Shaei; Pooyan, Shahriar; Wang, Jihong; Choudhury, Indrani; Leibowitz, Michael J.; Stein, Stanley J.

doi:10.1021/bc980038p

Cited by 30 publications

(33 citation statements)

References 8 publications

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“…In this case, the polymer with the unhindered disulfide bond exhibited a fairly short half-life of release, whereas the sterically hindered disulfide bond released its load about 100 times more slowly. [107] The influence of the kind of crosslinkage was also shown for another PEG-pLL system. Here, thiol groups were introduced into the block copolymers, either with the crosslinker SPDP or with Traut's reagent.…”

Section: Disulfides For the Attachment Of A Shielding Moietymentioning

confidence: 92%

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Delivery of Nucleic Acids via Disulfide‐Based Carrier Systems

et al. 2009

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Nucleic acids are not only expected to assume a pivotal position as "drugs" in the treatment of genetic and acquired diseases, but could also act as molecular cues to control the microenvironment during tissue regeneration. Despite this promise, the efficient delivery of nucleic acids to their side of action is still the major hurdle. One among many prerequisites for a successful carrier system for nucleic acids is high stability in the extracellular environment, accompanied by an efficient release of the cargo in the intracellular compartment. A promising strategy to create such an interactive delivery system is to exploit the redox gradient between the extra- and intracellular compartments. In this review, emphasis is placed on the biological rationale for the synthesis of redox sensitive, disulfide-based carrier systems, as well as the extra- and intracellular processing of macromolecules containing disulfide bonds. Moreover, the basic synthetic approaches for introducing disulfide bonds into carrier molecules, together with examples that demonstrate the benefit of disulfides at the individual stages of nucleic acid delivery, will be presented.

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Section: Disulfides For the Attachment Of A Shielding Moietymentioning

confidence: 92%

“…Further conjugation steps can be carried out with the second amino group of cystamine (Table 1). [106][107][108][109][110] …”

Section: Conversion Of Carboxyl Groupsmentioning

confidence: 99%

Delivery of Nucleic Acids via Disulfide‐Based Carrier Systems

et al. 2009

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“…Whereas the bioreversible disulfide bond had been proposed for reversibly appending the therapeutic agent to the carrier and delivering it to cellular targets (Huang et al, 1998), the present studies used the more stable amide bond for appending the reporter group, digoxigenin, as a surrogate drug substance. To achieve high affinity binding to fMLF receptors, we explored the concept of using multiple copies of this ligand on the carrier polymer.…”

Section: Introductionmentioning

confidence: 99%

Conjugates Bearing Multiple Formyl-Methionyl Peptides Display Enhanced Binding to but Not Activation of Phagocytic Cells

et al. 2002

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N -Formyl-methionyl peptides can specifically bind to surface receptors on phagocytic cells. A single copy of N-formyl-methionine-leucine-phenylalanine (fMLF) covalently linked to a poly(ethylene glycol)-based polymer displayed reduced binding avidity (K d = 190 nM) for differentiated HL-60 cells relative to free fMLF (K d = 28 nM). Increasing the number of fMLF residues (up to eight) attached to a single polymer results in enhanced avidity for these cells (K d = 0.18 nM), which appears to be independent of whether the polymer backbone is linear or branched. However, no conjugate showed enhanced ability to activate phagocytic cells, relative to the free peptide (EC 50 = 5 nM), as measured by transient stimulation of release of calcium ions from intracellular stores into the cytoplasm. A polymer bearing four fMLF and four digoxigenin residues showed specific enhancement in binding to differentiated HL-60 cells and mouse peritoneal macrophages in situ relative to a polymer lacking fMLF; no such enhancement was seen in binding to receptor-negative lymphocytic Jurkat cells. These results suggest that multiple fMLF residues linked to a drug-delivery polymer can be used to target appended drugs to phagocytic cells with relatively little toxicity due to cellular activation.

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“…Covalent hitching of proteins, drugs, or DNA onto PTDs may circumvent conventional limitations by allowing to transport these compounds into a wide variety of cells in vitro and in vivo (7,8,(18)(19)(20)(21). TAT peptide chemically attached to various proteins (horseradish peroxidase, ␤-galactosidase, and some others) was able to deliver these proteins to various cells and even in tissues in mice with high levels in heart, lung, and spleen (7).…”

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confidence: 99%