5 research outputs found
Enhancing the Efficacy of CAR T Cells in the Tumor Microenvironment of Pancreatic Cancer
Pancreatic cancer has the worst prognosis and lowest survival rate among all types of cancers and thus, there exists a strong need for novel therapeutic strategies. Chimeric antigen receptor (CAR)-modified T cells present a new potential option after successful FDA-approval in hematologic malignancies, however, current CAR T cell clinical trials in pancreatic cancer failed to improve survival and were unable to demonstrate any significant response. The physical and environmental barriers created by the distinct tumor microenvironment (TME) as a result of the desmoplastic reaction in pancreatic cancer present major hurdles for CAR T cells as a viable therapeutic option in this tumor entity. Cancer cells and cancer-associated fibroblasts express extracellular matrix molecules, enzymes, and growth factors, which can attenuate CAR T cell infiltration and efficacy. Recent efforts demonstrate a niche shift where targeting the TME along CAR T cell therapy is believed or hoped to provide a substantial clinical added value to improve overall survival. This review summarizes therapeutic approaches targeting the TME and their effect on CAR T cells as well as their outcome in preclinical and clinical trials in pancreatic cancer
Mixing Matrix-corrected Whole-body Pharmacokinetic Modeling Using Longitudinal Micro-computed Tomography and Fluorescence-mediated Tomography
Purpose!#!Pharmacokinetic modeling can be applied to quantify the kinetics of fluorescently labeled compounds using longitudinal micro-computed tomography and fluorescence-mediated tomography (μCT-FMT). However, fluorescence blurring from neighboring organs or tissues and the vasculature within tissues impede the accuracy in the estimation of kinetic parameters. Contributions of elimination and retention activities of fluorescent probes inside the kidneys and liver can be hard to distinguish by a kinetic model. This study proposes a deconvolution approach using a mixing matrix to model fluorescence contributions to improve whole-body pharmacokinetic modeling.!##!Procedures!#!In the kinetic model, a mixing matrix was applied to unmix the fluorescence blurring from neighboring tissues and blood vessels and unmix the fluorescence contributions of elimination and retention in the kidney and liver compartments. Accordingly, the kinetic parameters of the hepatobiliary and renal elimination routes and five major retention sites (the kidneys, liver, bone, spleen, and lung) were investigated in simulations and in an in vivo study. In the latter, the pharmacokinetics of four fluorescently labeled compounds (indocyanine green (ICG), HITC-iodide-microbubbles (MB), Cy7-nanogels (NG), and OsteoSense 750 EX (OS)) were evaluated in BALB/c nude mice.!##!Results!#!In the simulations, the corrected modeling resulted in lower relative errors and stronger linear relationships (slopes close to 1) between the estimated and simulated parameters, compared to the uncorrected modeling. For the in vivo study, MB and NG showed significantly higher hepatic retention rates (P<0.05 and P<0.05, respectively), while OS had smaller renal and hepatic retention rates (P<0.01 and P<0.01, respectively). Additionally, the bone retention rate of OS was significantly higher (P<0.01).!##!Conclusions!#!The mixing matrix correction improves pharmacokinetic modeling and thus enables a more accurate assessment of the biodistribution of fluorescently labeled pharmaceuticals by μCT-FMT
Balancing Passive and Active Targeting to Different Tumor Compartments Using Riboflavin-Functionalized Polymeric Nanocarriers
Riboflavin
transporters (RFTs) and the riboflavin carrier protein (RCP) are highly
upregulated in many tumor cells, tumor stem cells, and tumor neovasculature,
which makes them attractive targets for nanomedicines. Addressing
cells in different tumor compartments requires drug carriers, which
are not only able to accumulate via the EPR effect but also to extravasate,
target specific cell populations, and get internalized by cells. Reasoning
that antibodies are among the most efficient targeting systems developed
by nature, we consider their size (∼10–15 nm) to be
ideal for balancing passive and active tumor targeting. Therefore,
small, short-circulating (10 kDa, ∼7 nm, <i>t</i><sub>1/2</sub> ∼ 1 h) and larger, longer-circulating (40 kDa,
∼13 nm, <i>t</i><sub>1/2</sub> ∼ 13 h) riboflavin-targeted
branched PEG polymers were synthesized, and their biodistribution
and target site accumulation were evaluated in mice bearing angiogenic
squamous cell carcinoma (A431) and desmoplastic prostate cancer (PC3)
xenografts. The tumor accumulation of the 10 kDa PEG was characterized
by rapid intercompartmental exchange and significantly improved upon
active targeting with riboflavin (RF). The 40 kDa PEG accumulated
in tumors four times more efficiently than the small polymer, but
its accumulation did not profit from active RF-targeting. However,
RF-targeting enhanced the cellular internalization in both tumor models
and for both polymer sizes. Interestingly, the nanocarriers’
cell-uptake in tumors was not directly correlated with the extent
of accumulation. For example, in both tumor models the small RF-PEG
accumulated much less strongly than the large passively targeted PEG
but showed significantly higher intracellular amounts 24 h after iv
administration. Additionally, the size of the polymer determined its
preferential uptake by different tumor cell compartments: the 10 kDa RF-PEGs most efficiently targeted cancer cells, whereas the highest
uptake of the 40 kDa RF-PEGs was observed in tumor-associated macrophages.
These findings imply that drug carriers with sizes in the range of
therapeutic antibodies show balanced properties with respect to passive
accumulation, tissue penetration, and active targeting. Besides highlighting
the potential of RF-mediated (cancer) cell targeting, we show that
strong tumor accumulation does not automatically mean high cellular
uptake and that the nanocarriers’ size plays a critical role
in cell- and compartment-specific drug targeting