title: Liposomal doxorubicin extravasation controlled by phenotype-specific transport properties of tumor microenvironment and vascular barrier.
abstract: Although nanotherapeutics can be advantageous over free chemotherapy, the benefits of drug vectors can vary from patient to patient based on differences in tumor microenvironments. Although systemic pharmacokinetics (PK) of drugs is considered as the major determinant of its efficacy in clinics, recent clinical and basic research indicates that tumor-based PK can provide better representation of therapeutic efficacy. Here, we have studied the role of the tumor extravascular tissue in the extravasation kinetics of doxorubicin (DOX), delivered by pegylated liposomes (PLD), to murine lung (3LL) and breast (4T1) tumors. We found that phenotypically different 3LL and 4T1 tumors shared the similar systemic PK, but DOX extravasation in the tumor extravascular tissue was substantially different. Liquid chromatography-mass spectrometry (LC-MS) measurements showed that DOX fluorescence imaged by fluorescence microscopy could be used as a marker to study tumor microenvironment PK, providing an excellent match to DOX kinetics in tumor tissues. Our results also suggest that therapeutic responses can be closely related to the interplay of concentration levels and exposure times in extravascular tissue of tumors. Finally, the computational model of capillary drug transport showed that internalization of drug vectors was critical and could lead to 2-3 orders of magnitude more efficient drug delivery into the extravascular tissue, compared to non-internalized localization of drug vectors, and explaining the differences in therapeutic efficacy between the 3LL and 4T1 tumors. These results show that drug transport and partitioning characteristics can be phenotype- and microenvironment-dependent and are highly important in drug delivery and therapeutic efficacy.
authors.affiliation: The Houston Methodist Research Institute, Houston, TX 77030, United States.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yokoi
authors.affiliation: The Houston Methodist Research Institute, Houston, TX 77030, United States.
authors.forename: Diana
authors.initials: D
authors.lastname: Chan
authors.affiliation: The Houston Methodist Research Institute, Houston, TX 77030, United States; Belgrade Metropolitan University, Research and Development Center for Bioengineering, 3400 Kragujevac, Serbia; Serbian Academy of Sciences and Arts, 11000 Belgrade, Serbia.
authors.forename: Milos
authors.initials: M
authors.lastname: Kojic
authors.affiliation: The Houston Methodist Research Institute, Houston, TX 77030, United States; Belgrade Metropolitan University, Research and Development Center for Bioengineering, 3400 Kragujevac, Serbia.
authors.forename: Miljan
authors.initials: M
authors.lastname: Milosevic
authors.affiliation: The Houston Methodist Research Institute, Houston, TX 77030, United States.
authors.forename: David
authors.initials: D
authors.lastname: Engler
authors.affiliation: The Houston Methodist Research Institute, Houston, TX 77030, United States.
authors.forename: Rise
authors.initials: R
authors.lastname: Matsunami
authors.affiliation: The Houston Methodist Research Institute, Houston, TX 77030, United States.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tanei
authors.affiliation: The Houston Methodist Research Institute, Houston, TX 77030, United States.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Saito
authors.affiliation: The Houston Methodist Research Institute, Houston, TX 77030, United States.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: The Houston Methodist Research Institute, Houston, TX 77030, United States. Electronic address: aziemys@houstonmethodist.org.
authors.forename: Arturas
authors.initials: A
authors.lastname: Ziemys
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy*; D010641:Phenotype; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000627:therapeutic use; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Computational diffusion model; Doxorubicin; Drug vector; Kinetics; Liposome; Nanotherapeutics