Poly(ethylene glycol)-Prodrug Conjugates: Concept, Design, and Applications

Banerjee, Soumik; Aher, Naval D.; Patil, Rajesh B.; Khandare, Jayant

doi:10.1155/2012/103973

Cited by 240 publications

(186 citation statements)

References 90 publications

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“…It has been reported that the physiological activity of α-factor pheromone is closely correlated with affinity for the phospholipid membrane. [36][37][38] Since the target of α-factor is a membrane-associated protein, Ste2p receptor, a certain type of hydrophobic moiety attached to α-factor could aid pheromone localization to the target cell membrane, as do many other hormone such as Ras protein, 29,36-38 thereby leading to increased probability of binding. However, integration of a pheromone into the cellular lipid bilayer depends on the type of modification applied.…”

Section: Discussionmentioning

confidence: 99%

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Highly Active Analogs of α-Factor and Their Activities Against Saccharomyces cerevisiae

Ahn¹,

Hong²,

Jin³

et al. 2014

Bulletin of the Korean Chemical Society

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Thirteen analogs of tridecapeptide α-factor (WHWLQLKPGQPMY) of Saccharomyces cerevisiae with C-or N-terminal Trp extension and isosteric replacement by Aib at position 8 and 11, Trp at position 13, D-Ala at position 9, and Orn and Glu at position 6 were synthesized and assayed for their biological activity. Receptor binding assay was carried out using our newly developed spectrophotometric method with detector peptide 14. C-or N-terminal extended analogs, α-factor-[Trp] n (n =1-5) 1-5 and [N-Trp] 1 -α-factor 6, were all less active than native α-factor and gradual decreases in both activity and receptor affinity were observed with greater Trp extension. Trp-substituted analog at position 13, [Trp 13 ]α-factor 7, exhibited about 2-fold reductions in both activity and receptor affinity. Aib-substituted analogs, [Aib 8 ]α-factor 8 and [Aib 11]α-factor 9, showed 5-to 10-fold reduction in activity as well as 3-fold reduction in receptor affinity compared to native α-factor. [Orn 6]α-factor 10 demonstrated strong potency with a 7.0-fold increase in halo activity as well as 1.8-fold increase in receptor affinity compared to native α-factor. ]α-factor 11 exhibited 15-fold higher halo activity as well as nearly 3-fold higher receptor affinity compared to native α-factor.

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Section: Discussionmentioning

confidence: 99%

“…However, integration of a pheromone into the cellular lipid bilayer depends on the type of modification applied. 21,[36][37][38] Alanine scanning study previously examined the roles of C-and N-terminal residues of α-factor in pheromone activity and receptor binding affinity.…”

Section: Discussionmentioning

confidence: 99%

Highly Active Analogs of α-Factor and Their Activities Against Saccharomyces cerevisiae

Ahn¹,

Hong²,

Jin³

et al. 2014

Bulletin of the Korean Chemical Society

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“…However, the ideal promoiety remains to be chosen. Poly(ethylene glycol) chains are a strong candidate: their presence can increase aqueous solubility of hydrophobic drugs, prolong circulation time, slow down hydrolysis, and increase stability in the gastrointestinal tract [48][49][50][51][52][53]. This type of decoration is particularly valuable for protein/polypeptide drugs and drug-carrying liposomes (rev.s, e.g., [54][55][56][57][58][59]), which can be protected from phagocytosis and are less at risk of provoking an immune response.…”

Section: Introductionmentioning

confidence: 99%

N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol

et al. 2015

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Abstract:Resveratrol is a natural polyphenol with many interesting biological activities. Its pharmacological exploitation in vivo is, however, hindered by its rapid elimination via phase II conjugative metabolism at the intestinal and, most importantly, hepatic levels. One approach to bypass this problem relies on prodrugs. We report here the synthesis, characterization, hydrolysis, and in vivo pharmacokinetic behavior of resveratrol prodrugs in which the OH groups are engaged in an N-monosubstituted carbamate ester linkage. As promoiety, methoxy-oligo(ethylene glycol) groups (m-OEG) (CH3-[OCH2CH2]n-) of defined chain length (n = 3, 4, 6) were used. These are expected to modulate the chemico-physical properties of the resulting derivatives, much like longer poly(ethylene glycol) (PEG) chains, while retaining a relatively low MW and, thus, a favorable drug loading capacity. Intragastric administration to rats resulted in the appearance in the bloodstream of the prodrug and of the products of its partial hydrolysis, confirming protection from first-pass metabolism during absorption.

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“…9-11) and gene-directed enzyme prodrug therapy (GDEPT; refs. 6, 12, 13) as well as directly in prodrug monotherapy, which relies on the elevated levels of bG found in the tumor microenvironment (14)(15)(16) to selectively convert prodrug into active drug. For instance, Albin and colleagues reported that the level of bG human breast tumors was up to 6-times greater than that in normal tissues (17).…”

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confidence: 99%

PET Imaging of β-Glucuronidase Activity by an Activity-Based 124I-Trapping Probe for the Personalized Glucuronide Prodrug Targeted Therapy

Cheng

Leu

et al. 2014

Molecular Cancer Therapeutics

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Beta-glucuronidase (bG) is a potential biomarker for cancer diagnosis and prodrug therapy. The ability to image bG activity in patients would assist in personalized glucuronide prodrug cancer therapy. However, whole-body imaging of bG activity for medical usage is not yet available. Here, we developed a radioactive bG activity-based trapping probe for positron emission tomography (PET). We generated a 124 I-tyramine-conjugated difluoromethylphenol beta-glucuronide probe (TrapG) to form 124 I-TrapG that could be selectively activated by bG for subsequent attachment of 124 I-tyramine to nucleophilic moieties near bG-expressing sites. We estimated the specificity of a fluorescent FITC-TrapG, the cytotoxicity of tyramine-TrapG, and the serum half-life of 124 I-TrapG. bG targeting of 124 I-TrapG in vivo was examined by micro-PET. The biodistribution of 131 I-TrapG was investigated in different organs. Finally, we imaged the endogenous bG activity and assessed its correlation with therapeutic efficacy of 9-aminocamptothecin glucuronide (9ACG) prodrug in native tumors. FITC-TrapG showed specific trapping at bG-expressing CT26 (CT26/mbG) cells but not in CT26 cells. The native TrapG probe possessed low cytotoxicity. 124 ITrapG preferentially accumulated in CT26/mbG but not CT26 cells. Meanwhile, micro-PET and wholebody autoradiography results demonstrated that 124 I-TrapG signals in CT26/mbG tumors were 141.4-fold greater than in CT26 tumors. Importantly, Colo205 xenografts in nude mice that express elevated endogenous bG can be monitored by using infrared glucuronide trapping probes (NIR-TrapG) and suppressed by 9ACG prodrug treatment. 124 I-TrapG exhibited low cytotoxicity allowing long-term monitoring of bG activity in vivo to aid in the optimization of prodrug targeted therapy.

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Poly(ethylene glycol)-Prodrug Conjugates: Concept, Design, and Applications

Cited by 240 publications

References 90 publications

Highly Active Analogs of α-Factor and Their Activities Against Saccharomyces cerevisiae

Highly Active Analogs of α-Factor and Their Activities Against Saccharomyces cerevisiae

N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol

PET Imaging of β-Glucuronidase Activity by an Activity-Based 124I-Trapping Probe for the Personalized Glucuronide Prodrug Targeted Therapy

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