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Encapsulation of Poorly Soluble Drugs in Polymer-Drug Conjugates: Effect of Dual-Drug Nanoformulations on Cancer Therapy

Authors
  • Senanayake, Thulani H.1
  • Lu, Yaman1
  • Bohling, Anna1
  • Raja, Srikumar2, 3
  • Band, Hamid2, 3
  • Vinogradov, Serguei V.1
  • 1 University of Nebraska Medical Center, Department of Pharmaceutical Sciences, College of Pharmacy, Omaha, Nebraska, 68198-6025, USA , Omaha (United States)
  • 2 University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases and UNMC-Eppley Cancer Center, Omaha, Nebraska, 68198-6025, USA , Omaha (United States)
  • 3 University of Nebraska Medical Center, Department of Biochemistry and Molecular Biology, College of Medicine, Omaha, Nebraska, 68198-6025, USA , Omaha (United States)
Type
Published Article
Journal
Pharmaceutical Research
Publisher
Springer-Verlag
Publication Date
Jan 23, 2014
Volume
31
Issue
6
Pages
1605–1615
Identifiers
DOI: 10.1007/s11095-013-1265-3
Source
Springer Nature
Keywords
License
Yellow

Abstract

PurposeCurrent 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.MethodsPCL 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.ResultsCPVA-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.ConclusionOral dual-drug nanoformulations of poorly-soluble drugs proved to be a highly efficient combination anticancer therapy in preclinical studies.

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