TY - JOUR
T1 - Hyperbranched polymer-drug conjugates with high drug payload for enhanced cellular delivery
AU - Kolhe, Parag
AU - Khandare, Jayant
AU - Pillai, Omathanu
AU - Kannan, Sujatha
AU - Lieh-Lai, Mary
AU - Kannan, Rangaramanujam
N1 - Funding Information:
This research work was funded by National Science Foundation through DMR grant no. 9876221, Institute of Manufacturing Research (Wayne State University), Children’s Research Center of Michigan (Children’s Hospital of Michigan), and NICHD Pediatric Research Unit Network NIH 5U01HD 37261-04. We are grateful to Prof. David Bas-sett for help with FACS and Prof. Raymond Iezzi for the help with fluorescence microscopy.
PY - 2004/12
Y1 - 2004/12
N2 - Purpose. To synthesize and evaluate hyperbranched polymer (HBP)-drug conjugates with high drug payload for enhanced cellular delivery. Methods. Polyol- and polyglycerol-ibuprofen conjugates with or without imaging agent fluorescein isothiocyanate (FITC) were synthesized using dicyclohexilcarbodiimide (DCC) as a coupling agent. Drug-polymer conjugates were characterized using 13C NMR, 1H NMR, and gel permeation chromatography (GPC). Stability of the drug-conjugates was studied using free drug release through a dialysis membrane. Cellular entry of FITC-labeled HBP conjugates was studied using fluorescence activated cell sorter (FACS), and cell supernatant was analyzed by UV-visible spectrophotometer. The intracellular localization of FITC-labeled conjugates in A549 lung epithelial cells was imaged using fluorescence microscopy. Anti-inflammatory activity of the HBP-ibuprofen conjugates was estimated in vitro by measuring the concentration of prostaglandin (PGE2) using an ELISA kit. Results. The average number of ibuprofen molecules conjugated per molecule of HBP was estimated to be 50 for polyol and 53 for polyglycerol. The HBP-drug conjugates did not release the drug up to 72 h in methanol, indicating the presence of stable ester bonds. Both the polymer-drug conjugates entered the cells rapidly. The conjugates were localized in the cell cytosol as evidenced by fluorescence microscopy. Within 30 min, the HBP-drug conjugates showed rapid suppression of PGE2 synthesis, whereas free ibuprofen did not show any activity. At later times, the conjugates showed comparable activity. Conclusions. For the first time, we report HBP conjugates with a high drug payload. HBP-drug conjugates entered the cells rapidly and produced the desired pharmacological action. This study demonstrates that hyperbranched polyol and polyglycerol are promising nanovehicles for achieving enhanced cellular delivery of drugs.
AB - Purpose. To synthesize and evaluate hyperbranched polymer (HBP)-drug conjugates with high drug payload for enhanced cellular delivery. Methods. Polyol- and polyglycerol-ibuprofen conjugates with or without imaging agent fluorescein isothiocyanate (FITC) were synthesized using dicyclohexilcarbodiimide (DCC) as a coupling agent. Drug-polymer conjugates were characterized using 13C NMR, 1H NMR, and gel permeation chromatography (GPC). Stability of the drug-conjugates was studied using free drug release through a dialysis membrane. Cellular entry of FITC-labeled HBP conjugates was studied using fluorescence activated cell sorter (FACS), and cell supernatant was analyzed by UV-visible spectrophotometer. The intracellular localization of FITC-labeled conjugates in A549 lung epithelial cells was imaged using fluorescence microscopy. Anti-inflammatory activity of the HBP-ibuprofen conjugates was estimated in vitro by measuring the concentration of prostaglandin (PGE2) using an ELISA kit. Results. The average number of ibuprofen molecules conjugated per molecule of HBP was estimated to be 50 for polyol and 53 for polyglycerol. The HBP-drug conjugates did not release the drug up to 72 h in methanol, indicating the presence of stable ester bonds. Both the polymer-drug conjugates entered the cells rapidly. The conjugates were localized in the cell cytosol as evidenced by fluorescence microscopy. Within 30 min, the HBP-drug conjugates showed rapid suppression of PGE2 synthesis, whereas free ibuprofen did not show any activity. At later times, the conjugates showed comparable activity. Conclusions. For the first time, we report HBP conjugates with a high drug payload. HBP-drug conjugates entered the cells rapidly and produced the desired pharmacological action. This study demonstrates that hyperbranched polyol and polyglycerol are promising nanovehicles for achieving enhanced cellular delivery of drugs.
KW - Cell entry
KW - Dendrimers
KW - Hyperbranched polymers
KW - Ibuprofen
KW - Polyglycerol
KW - Polyol
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U2 - 10.1007/s11095-004-7670-x
DO - 10.1007/s11095-004-7670-x
M3 - Article
C2 - 15648249
AN - SCOPUS:15244346848
VL - 21
SP - 2185
EP - 2195
JO - Pharmaceutical Research
JF - Pharmaceutical Research
SN - 0724-8741
IS - 12
ER -