Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan.
Liposomes improve the pharmacokinetics and safety of rapidly cleared drugs, but have not yet improved the clinical efficacy compared to the non-encapsulated drug. This inability to improve efficacy may be partially due to the non-uniform distribution of liposomes in solid tumors. The tumor extra-cellular matrix is a barrier to distribution and includes the high molecular weight glycosaminoglycan, hyaluronan (HA). Strategies to remove HA or block its synthesis may improve drug delivery into solid tumors. Orally administered methylumbelliferone (MU) is an inhibitor of HA synthesis, but it is limited by low potency and limited solubility. In this study, we encapsulate a water-soluble phosphorylated prodrug of MU (MU-P) in a liposome (L-MU-P). We demonstrate that L-MU-P is a more potent inhibitor of HA synthesis than oral MU in the 4T1 murine mammary carcinoma model using both a quantitative ELISA and histochemistry. We show that HA depletion improves the tumor distribution of liposomes computed using Mander's colocalization analysis of liposomes with the tumor vasculature. Hyaluronan depletion also increases the fraction of the tumor area positive for liposomes. This improved distribution extends the overall survival of mice treated with Doxil®.
The UC-Berkeley-UCSF Graduate Program in Bioengineering, University of California Berkeley, Berkeley 94720, USA; Department of Bioengineering, Therapeutic Sciences and Pharmaceutical Chemistry, University of California San Francisco, San Francisco 94143, USA.
Aditya G
AG
Kohli
Department of Bioengineering, Therapeutic Sciences and Pharmaceutical Chemistry, University of California San Francisco, San Francisco 94143, USA.
Saul
S
Kivimäe
Department of Bioengineering, Therapeutic Sciences and Pharmaceutical Chemistry, University of California San Francisco, San Francisco 94143, USA; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco 94143, USA.
Matthew R
MR
Tiffany
The UC-Berkeley-UCSF Graduate Program in Bioengineering, University of California Berkeley, Berkeley 94720, USA; Department of Bioengineering, Therapeutic Sciences and Pharmaceutical Chemistry, University of California San Francisco, San Francisco 94143, USA; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco 94143, USA. Electronic address: szoka@cgl.ucsf.edu.
Francis C
FC
Szoka
D000284:Administration, Oral; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006820:Hyaluronic Acid / Q000172:deficiency*; D006923:Hymecromone / Q000008:administration & dosage* / Q000737:chemistry; D007275:Injections, Intravenous; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D012995:Solubility; D013997:Time Factors; D059016:Tumor Microenvironment
D000903:Antibiotics, Antineoplastic; D011355:Prodrugs; C506643:liposomal doxorubicin; D006923:Hymecromone; D011092:Polyethylene Glycols; D004317:Doxorubicin; D006820:Hyaluronic Acid
Breast cancer; Extra-cellular matrix; Liposomes; Tumor penetration