Hyperbranched polymer-drug conjugates with high drug payload for enhanced cellular delivery

Parag Kolhe, Jayant Khandare, Omathanu Pillai, Sujatha Kannan, Mary Lieh-Lai, Rangaramanujam Kannan

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2185-2195
Number of pages11
JournalPharmaceutical Research
Volume21
Issue number12
DOIs
StatePublished - Dec 2004
Externally publishedYes

Keywords

  • Cell entry
  • Dendrimers
  • Hyperbranched polymers
  • Ibuprofen
  • Polyglycerol
  • Polyol

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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