Abstract
Graft copolymer composed hyaluronic acid (HA) and poly(d,l-lactide-co-glycolide) (PLGA) (HAgLG) was synthesized for antitumor targeting via CD44 receptor of tumor cells. The carboxylic end of PLGA was conjugated with hexamethylenediamine (HMDA) to have amine end group in the end of chain (PLGA-amine). PLGA-amine was coupled with carboxylic acid of HA. Self-assembled polymeric micelles of HAgLG have spherical morphologies and their sizes were around 50–200 nm. Doxorubicin (DOX)-incorporated polymeric micelles were prepared by dialysis procedure. DOX was released over 4 days and its release rate was accelerated by the tumoric enzyme hyaluronidase. To assess targetability of polymeric micelles, CD44-positive HepG2 cells were employed treated with fluorescein isothiocyanate (FITC)-labeled polymeric micelles. HepG2 cells strongly expressed green fluorescence at the cell membrane and cytosol. However, internalization of polymeric micelles were significantly decreased when free HA was pretreated to block the CD44 receptor. Furthermore, the CD44-specific anticancer activity of HAgLG polymeric micelles was confirmed using CD44-negative CT26 cells and CD44-positive HepG2 cells. These results indicated that polymeric micelles of HaLG polymeric micelles have targetability against CD44 receptor of tumor cells. We suggest HAgLG polymeric micelles as a promising candidate for specific drug targeting.
Highlights
Self-assembling properties of amphiphilic macromolecules have been extensively investigated for drug targeting because they have drug carrying potential to a specific site of the human body or cells [1,2,3].Especially, polymeric micelles or core-shell type nanoparticles have unique structural properties, i.e., polymeric micelles have a hydrophobic inner-core and hydrated outer-shell structure
To synthesize hyaluronic acid (HA) and PLGA (HAgLG) copolymer, carboxylic group of PLGA was aminated with hexamethylene diamine (HMDA) and aminated PLGA was conjugated with carboxylic acid group of HA with the aid of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC)
Fluorescence intensity of CT26 cells was not significantly changed by blocking of CD44 receptor (Figure 7a,b). These results indicated that HAgLG polymeric micelles can be delivered through CD44 receptor of HepG2 cells
Summary
Self-assembling properties of amphiphilic macromolecules have been extensively investigated for drug targeting because they have drug carrying potential to a specific site of the human body or cells [1,2,3]. Inner-core of the polymeric micelles can act as a drug incorporation domain and hydrated outer-shell is normally helpful to avoid unwanted uptake by reticuloendothelial system (RES) [1]. HA receptors such as CD44 and RHAMM are over-expressed at malignant cells having high mobility and invasive capacity [9,10]. From this point of view, HA has been extensively used as a targeting molecule for CD44 receptor of tumor cells or invasive tumor cells [4,5,11,12,13].
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