Targeted delivery of doxorubicin by HPMA copolymer-hyaluronan bioconjugates.
OBJECTIVE
Overexpression of hyaluronan (HA) receptors on cancer cells results in enhanced endocytotic uptake of the drug conjugate. An N-(2-hydroxypropyl)methacrylamide (HPMA)-HA polymeric drug delivery system was used for targeted delivery of doxorubicin to cancer cells.


METHODS
HA-doxorubicin (DOX) bioconjugates (HA-DOX), and HPMA copolymer-DOX conjugates containing HA as a side chain (HPMA-HA-DOX) were synthesized. The cytotoxicity of the polymer-drug conjugate was evaluated via in vitro cell culture. The internalization of the conjugate was visualized by fluorescence microscopy.


RESULTS
Cytotoxicity of HPMA-HA-DOX targeted bioconjugate was higher against human breast cancer (HBL-100), ovarian cancer (SKOV-3), and colon cancer (HCT-116) cells when compared to the non-targeted HPMA-DOX conjugate. Fluorescence confocal microscopy revealed that the targeted HPMA-HA-DOX conjugates were internalized more efficiently by cancer cells relative to the non-targeted HPMA-DOX conjugate. Both HPMA-DOX and HPMA-HA-DOX showed minimal cytotoxicity toward mouse fibroblast NIH 3T3 cells. The internalization of polymer conjugates was correlated with their cytotoxicity.


CONCLUSIONS
Selective delivery of anti-cancer agents to cancer cells was achieved by biochemical targeting. The HA-modified HPMA copolymer showed improved toxicity due to receptor-mediated uptake of the macromolecular drug.
Luo
Yi
Y
Department of Medicinal Chemistry, The University of Utah, Salt Lake City, USA.
Bernshaw
Nicole J
NJ
Lu
Zheng-Rong
ZR
Kopecek
Jindrich
J
Prestwich
Glenn D
GD
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000493:pharmacokinetics*; D008689:Methacrylates / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D008689:Methacrylates; D011108:Polymers; D004317:Doxorubicin; D006820:Hyaluronic Acid; C032802:hydroxypropyl methacrylate