Encapsulation of Poorly Soluble Drugs in Polymer-Drug Conjugates: Effect of Dual-Drug Nanoformulations on Cancer Therapy
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Current cancer chemotherapy is gradually shifting to the application of drug combinations that prevent development of drug resistance. Many anticancer drugs have poor solubility and limited oral bioavailability. Using an innovative approach, we developed dual-drug nanoformulations of a polymeric nanogel conjugate with anticancer 5-FU nucleoside analog, floxuridine (FLOX), and the second anticancer drugs, paclitaxel (PCL), or a geldanamycin analog, 17-AAG, for combination therapy.
PCL or 17-AAG had been encapsulated in the cholesteryl-polyvinyl alcohol-floxuridine nanogel (CPVA-FLOX) by simple solution mixing and sonication. Dual nanodrugs formed particles with diameter 180 nm and either drug content (5–20%) that were stable and could be administered orally. Their cytotoxicity in human and mouse cancer cells was determined by MTT assay, and cellular target inhibition – by Western blot analysis. Tumor growth inhibition was evaluated using an orthotopic mouse mammary 4T1 cancer model.
CPVA-FLOX was more potent than free drug in cancer models including drug-resistant ones; while dual nanodrugs demonstrated a significant synergy (CPVA-FLOX/PCL), or showed no significant synergy (CPVA-FLOX/17-AAG) compared to free drugs (PCL or 17-AAG). Dual nanodrug CPVA-FLOX/17-AAG effect on its cellular target (HSP70) was similar to 17-AAG alone. In animal model, however, both dual nanodrugs effectively inhibited tumor growth compared to CPVA-FLOX after oral administration.
Oral dual-drug nanoformulations of poorly-soluble drugs proved to be a highly efficient combination anticancer therapy in preclinical studies.
KEY WORDS17-AAG dual-drug nanoformulations floxuridine oral delivery paclitaxel
Acknowledgments and Disclosures
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under R01 award numbers CA136921 (for S.V.V.), CA116552, CA99163, CA87986 and CA105489 (for H.B.) and DODW81XWH-11-1-0167 (for H.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. S.M.R. acknowledges support from Nebraska Department of Health and Human Services and Nebraska Center for Nanomedicine-Center for Biomedical Research Excellence (NCN-COBRE seed grant). The authors thank Tom Bargar for assistance with transmission electron microscopy (UNMC Core), and Xin Wei for valuable help with some cell cultures.
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