Advances in PEGylation of important biotech molecules: delivery aspects

Ryan, Sinéad M.; Mantovani, Giuseppe; Wang, Xuexuan; Haddleton, David M.; Brayden, David J.

doi:10.1517/17425247.5.4.371

Cited by 290 publications

(207 citation statements)

References 99 publications

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“…1B). Assuming first order for transfers, the system of ODE defining Model II is: dy 1 /dt = -k 12 y 1 + k 21 y 2 -k deg y 1 + k rel y 3 (Eq. 3) dy 2 /dt = k 12 y 1 -k 21 y 2 (Eq.…”

Section: Two Compartmental Model Analysis Of Sct-polymer Derivatives mentioning

confidence: 99%

“…One of the most successful commercial approaches has been the covalent attachment of poly(ethylene glycol), i.e. PEGylation [3,4]. Improved PK is largely attributed to the increased molecular size conferred by PEG on the conjugate, thereby masking the protein surface from proteolytic attack, decreased recognition by phagocytes of the RES, and reduced glomerular filtration [5].…”

Section: Introductionmentioning

confidence: 99%

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PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

Ryan

Frías²,

Wang

et al. 2011

Journal of Controlled Release

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Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel combed-shaped endfunctionalised poly(PEG) methyl ether methacrylate) (sCT-P) comb-shaped polymers, to yield conjugates of total molecular weights (MW) inclusive of sCT: 6.5, 9.5, 23 and 40 kDa. The conjugates were characterised by HPLC and their in vitro and in vivo bioactivity was measured by cAMP assay on human T47D cells and following intravenous (i.v.) injection to rats, respectively. Stability against endopeptidases, rat serum and liver homogenates was assessed. There were linear and exponential relationships between conjugate MW with potency and efficacy respectively, however the largest MW conjugate still retained 70% of E max and an EC 50 of 3.7 nM. In vivo, while free sCT and the conjugates reduced serum [calcium] to a maximum of 15-30 % over 240 min, the half life (T½) was increased and the area under the curve (AUC) was extended in proportion to conjugate MW. Likewise, the polymer conferred protection on sCT against attack by trypsin, chymotrypsin, elastase, rat serum and liver homogenates, with the best protection afforded by sCT-P (40 kDa). Mathematical modelling accurately predicted the MW relationships to in vitro efficacy, potency, in vivo PK and enzymatic stability. With a significant increase in T½ for sCT, the 40 kDa MW comb-shaped PEG conjugate of sCT may have potential as a long-acting injectable formulation.

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“…1B). Assuming first order for transfers, the system of ODE defining Model II is: dy 1 /dt = -k 12 y 1 + k 21 y 2 -k deg y 1 + k rel y 3 (Eq. 3) dy 2 /dt = k 12 y 1 -k 21 y 2 (Eq.…”

Section: Two Compartmental Model Analysis Of Sct-polymer Derivatives mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

Ryan

Frías²,

Wang

et al. 2011

Journal of Controlled Release

Self Cite

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show abstract

“…This polymer is highly soluble in aqueous solution and is approved for use by the Food and Drug Administration (FDA) as a result of its non-toxic, non-immunogenic and non-antigenic properties [57] . It has since been used extensively, to improve the pharmacokinetic and pharmacodynamic properties of drugs including biologicals, and as a component in gene delivery constructs [57][58][59][60] . PEGylation is generally used to increase the water solubility of molecules, prolong their systemic circulation, limit toxicity in addition to avoiding uptake by the RES [57][58][59][60] .…”

Section: Serum Stabilitymentioning

confidence: 99%

Therapeutic targeting in the silent era: advances in non-viral siRNA delivery

et al. 2010

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Access to the full text of the published version may require a subscription. Rights AbstractGene silencing using RNA-interference, first described in mammalian systems almost a decade ago, is revolutionizing therapeutic target validation efforts both in vitro and in vivo. Moreover, the potential for using short interfering RNA (siRNA) as a therapy in its own right is also progressing at a significant pace. However, the widespread use of such approaches is contingent on having appropriate delivery systems to achieve clinically appropriate, safe, and efficient delivery of siRNA. There are many physicochemical and biological barriers to such delivery, and a growing emphasis on the design and characterisation of non-viral technologies that will overcome these barriers and expedite targeted delivery. This review discusses the considerations and challenges associated with use of siRNA-based therapeutics, including stability and off-target effects. Speculation is made on the properties of an ideal delivery system and the non-viral delivery approaches used to date, both in vitro and in vivo, are classified and discussed. Moreover, the ability of cyclodextrin-based delivery vectors to fulfil many of the criteria of an ideal delivery construct is also elaborated.3 Introduction:

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“…[1,2] However, the therapeutic potency of siRNA is severely limited by delivery problems. [2][3][4][5] PEGylation, a technique commonly used to improve the in vivo pharmacokinetics of protein therapeutics, [6,7] has also been investigated for siRNA delivery. [8][9][10][11][12][13][14][15][16] Covalent conjugation of a PEG chain to siRNA has shown to increase serum stability of siRNA with sufficient gene silencing efficiency.…”

Section: Introductionmentioning

confidence: 99%

“…[6,17,18] Recently, comb-like PEG polymers, i.e., polyethylene glycol grafted poly(meth)acrylates, have proved to be potent alternatives to linear and branched PEG for improving the pharmacokinetics of protein drugs. [18][19][20] When compared to the linear PEG with equivalent molecular weights, the comb-like PEG displays greater steric hindrance, thus potentially enhancing biostability and lowering clearance rates of the conjugated biotherapeutics.…”

Section: Introductionmentioning

confidence: 99%

Conjugation of siRNA with Comb‐Type PEG Enhances Serum Stability and Gene Silencing Efficiency

Gunasekaran

Nguyen

Maynard

et al. 2011

Macromol. Rapid Commun.

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A thiol‐modified siRNA targeting the enhanced green fluorescence protein (eGFP) gene was conjugated with RAFT‐synthesized, pyridyl disulfide‐functional poly(PEG methyl ether acrylate)s (p(PEGA)s). siRNA‐p(PEGA) conjugates demonstrated significantly enhanced in vitro serum stability and nuclease resistance compared to the unmodified and thiol‐modified siRNA. The complexes of siRNA‐p(PEGA) conjugates with a fusogenic peptide, KALA ((+)/(–) = 2) inhibited the protein expression approximately 28‐fold more than the KALA complex of the unmodified siRNA. The protein inhibition caused by siRNA‐p(PEGA)‐KALA complexes (56 ± 5%–58 ± 3% of the fluorescence expressed in non‐treated cells) was comparable to the effect of the unmodified siRNA‐lipofectamine complex (77 ± 7%). magnified image

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Advances in PEGylation of important biotech molecules: delivery aspects

Cited by 290 publications

References 99 publications

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

Therapeutic targeting in the silent era: advances in non-viral siRNA delivery

Conjugation of siRNA with Comb‐Type PEG Enhances Serum Stability and Gene Silencing Efficiency

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