Release from polymeric prodrugs: Linkages and their degradation

D'Souza, Ajit Joseph M.; Topp, Elizabeth M.

doi:10.1002/jps.20096

Cited by 134 publications

(84 citation statements)

References 103 publications

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“…Because of elevated expression of FR on various types of tumor cells and activated macrophages, folic acid has been exploited extensively as a drug delivery vehicle for cancer and inflammatory diseases (25)(26)(27)(28)(29). Because higher potencies are achieved generally when the drug is released from its attached targeting ligand (i.e., folic acid) in an unaltered form (30)(31)(32)(33), the data presented here suggest that disulfide bridges between folate and its therapeutic payload might constitute suitable linkers for site-specific drug release. This argument is supported by the much more potent antitumor activity of a disulfide-linked folate-mitomycin C conjugate relative to an analogus amide-linked conjugate (34,35).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging

Yang¹,

Chen

Vlahov

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

290

244

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Despite functional evidence for disulfide bond-reducing activity in endosomal compartments, the mechanistic details pertaining to such process (e.g., kinetics and sites of disulfide reduction) remain largely controversial. To address these questions directly, we have synthesized a previously uncharacterized fluorescent folate conjugate, folate-(BODIPY FL)-SS-rhodamine (folate-FRET), that changes fluorescence from red to green upon disulfide bond reduction. Using this construct, we have observed that disulfide reduction: (i) occurs with a half-time of 6 h after folate-FRET endocytosis, (ii) begins in endosomes and does not depend significantly on redox machinery located on the cell surface or within the lysosome or the Golgi apparatus, (iii) occurs independently of endocytic vesicle trafficking along microtubules, and (iv) yields products that are subsequently sorted into distinct endosomes and trafficked in different directions. Finally, colocalization of folate and transferrin receptors suggest that conclusions derived from this study may apply to other endocytic pathways.disulfide bond reduction ͉ endosome ͉ folate receptor ͉ drug targeting

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Section: Discussionmentioning

confidence: 99%

Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging

Yang¹,

Chen

Vlahov

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

290

244

View full text Add to dashboard Cite

show abstract

“…Low conjugation efficiencies were expected as multiple polymer and drug modifications were required to achieve the final products. Ester bonds are the most commonly used in literature due to ease of synthesis, and also represent hydrolytically labile bonds; amide-linked conjugates represent hydrolytically stable bonds, whereas hydrazone linkers are hydrolytically degraded at endosomal pH 5.0 but stable at physiological pH 7.4 [11,34]. In vitro cancer cell cytotoxicity studies in Figure 5A show that the cleavable conjugates, ester-linked DOX (DOXePVA) and hydrazone-linked DOX (DOXhPVA), are active against cancer cells, whereas the noncleavable amide-linked DOX (DOXaPVA) is not.…”

Section: Polymer-drug Linker Affects Drug Activitymentioning

confidence: 99%

“…Various large [1][2][3][4][5] and small [6][7][8] polymers have been considered for this application. In addition to molecular weight, properties such as net charge, drug loading and biodegradability can also be finely-tuned [4,[9][10][11][12][13][14][15]; however, the optimal properties which enable high therapeutic efficacies of anticancer drugs remain unclear, owing to the many variables which can dictate biological activity.…”

mentioning

confidence: 99%

Low-Molecular-Weight Polymer–Drug Conjugates for Synergistic Anticancer Activity of Camptothecin and Doxorubicin Combinations

Camacho

Menegatti

Mitragotri

2016

Nanomedicine (Lond.)

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Background: High-molecular-weight (MW) polymers (>50,000 Da) can be conjugated to chemotherapy drugs in order to improve their tumor accumulation, while low MW polymers ≤10,000 Da are often overlooked due to faster plasma clearance. Small polymers, however, may facilitate deeper tumor penetration. Materials & methods:Here, we investigate the anticancer efficacy of 10 kDa hyaluronic acid or poly(vinyl alcohol) conjugated to synergistic combinations of camptothecin and doxorubicin, with emphasis on chemical linker impacts. Results: Our results emphasize drug hydrolyzability for synergy preservation, and also demonstrate superior cancer cell inhibition with low MW polymer-drug conjugates. Conclusion: This study shows the high therapeutic potential of low MW polymer-drug conjugates for polychemotherapy delivery, and provides further insight into the development of polymer-drug therapeutics.

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“…For PEG 2000 -DSPE (Fig. 7a), DSPE and methoxypolyethylene glycol (2000) were linked by amide linkage which was very stable to (non) enzymatic hydrolysis and usually used as a choice to make permanent conjugates (27). For PEG 2000 -CHEMS (Fig.…”

Section: Discussionmentioning

confidence: 99%

Sustained Liver Targeting and Improved Antiproliferative Effect of Doxorubicin Liposomes Modified with Galactosylated Lipid and PEG-Lipid

Wang

et al. 2010

AAPS PharmSciTech

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Abstract. In this study, a cleavable PEG-lipid (methoxypolyethyleneglycol 2000-cholesteryl hemisuccinate, PEG 2000 -CHEMS) linked via ester bond and galactosylated lipid ((5-cholesten-3β-yl) 4-oxo-4-[2-(lactobionyl amido) ethylamido] butanoate, CHS-ED-LA) were used to modify doxorubicin (DOX) liposome. DOX was encapsulated into conventional liposomes (CL), galactosylated liposomes (modified with CHS-ED-LA, GalL), pegylated liposomes (modified with PEG 2000 -CHEMS, PEG-CL), and pegylated galactosylated liposomes (modified with CHS-ED-LA and PEG 2000 -CHEMS, PEG-GalL) using an ammonium sulfate gradient loading method and then intravenously injected to normal mice. Both PEG-GalL DOX and GalL DOX gave relatively high overall drug targeting efficiencies to liver ((T e ) liver ) and were mainly taken up by hepatocyte. However, PEG-GalL DOX showed unique "sustained targeting" characterized by slowed transfer of DOX to liver and reduced peak concentrations in the liver. The biodistribution and antitumor efficacy of various DOX preparations were studied in hepatocarcinoma 22 (H22) tumor-bearing mice. The inhibitory rate of PEG-GalL DOX to H22 tumors was up to 94%, significantly higher than that of PEG-CL DOX, GalL DOX, CL DOX, and free DOX, although the tumor distribution of DOX revealed no difference between PEG-GalL DOX and PEG-CL DOX. Meanwhile, the gradual increase in the liver DOX concentration due to the sustained uptake of PEG-GalL DOX formulations resulted in lower damage to liver. In conclusion, the present investigation indicated that double modification of liposomes with PEG 2000 -CHEMS, and CHS-ED-LA represents a potentially advantageous strategy in the therapy of liver cancers or other liver diseases.

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Release from polymeric prodrugs: Linkages and their degradation

Cited by 134 publications

References 103 publications

Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging

Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging

Low-Molecular-Weight Polymer–Drug Conjugates for Synergistic Anticancer Activity of Camptothecin and Doxorubicin Combinations

Sustained Liver Targeting and Improved Antiproliferative Effect of Doxorubicin Liposomes Modified with Galactosylated Lipid and PEG-Lipid

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