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Tumor Site-Dependent Transport Properties Determine Nanotherapeutics Delivery and Its Efficacy.

ABSTRACT: Insufficient delivery of systemically administered anticancer drugs to tumors can compromise therapeutic efficacy and develop drug delivery-based therapeutic resistance. Nanotherapeutics such as PEGylated liposomal doxorubicin (PLD) are designed to preferentially accumulate in tumors utilizing enhanced permeation and retention effect. However, their antitumor effects and resulting clinical outcomes are modest and heterogeneous among tumors. Here, we aimed to investigate whether the amount and efficacy of PLD delivered to tumors are tumor site dependent. We established orthotopic primary tumor or liver metastases models of murine breast cancer using 4 T1 cells. PLD showed significant therapeutic effects against tumors that grew in primary mammary sites but not in the liver. We found that differences in therapeutic efficacy were not because of the intrinsic biological resistance of cancer cells but rather were associated with tumor site-dependent differences in transport properties, such as the amount of PLD delivery, blood vessel function, relative vascular permeability, and mechanical pressure in tumors. Thus, transport properties in tumor is site dependent and can be used as phenotypic surrogate markers for tumor drug delivery and therapeutic efficacy.

SUBMITTER: Kai M

PROVIDER: S-EPMC6600803 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Tumor Site-Dependent Transport Properties Determine Nanotherapeutics Delivery and Its Efficacy.

Kai Megumi M Ziemys Arturas A Liu Yan Ting YT Kojic Milos M Ferrari Mauro M Yokoi Kenji K

Translational oncology 20190620 9

Insufficient delivery of systemically administered anticancer drugs to tumors can compromise therapeutic efficacy and develop drug delivery-based therapeutic resistance. Nanotherapeutics such as PEGylated liposomal doxorubicin (PLD) are designed to preferentially accumulate in tumors utilizing enhanced permeation and retention effect. However, their antitumor effects and resulting clinical outcomes are modest and heterogeneous among tumors. Here, we aimed to investigate whether the amount and ef ...[more]

PMID: 31228770

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Project description:BackgroundThe therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy.MethodsWe developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC.ResultsTransport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival.ConclusionGemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints.Trial registrationClinicaltrials.gov NCT01276613.FundingLustgarten Foundation (989161), Department of Defense (W81XWH-09-1-0212), NIH (U54CA151668, KCA088084).

Dataset Information

Tumor Site-Dependent Transport Properties Determine Nanotherapeutics Delivery and Its Efficacy.

Publications

Tumor Site-Dependent Transport Properties Determine Nanotherapeutics Delivery and Its Efficacy.

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