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WIREs Nanomed Nanobiotechnol
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Challenges in preclinical to clinical translation for anticancer carrier‐mediated agents

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Major advances in carrier‐mediated agents (CMAs), which include nanoparticles and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages over their small‐molecule counterparts, there is substantial variability in how individual CMA formulations and patient characteristics affect the pharmacology, pharmacokinetics (PK), and pharmacodynamics (PD) (efficacy and toxicity) of these agents. Development or selection of animal models is used to predict the effects within a particular human disease. A breadth of studies have begun to emphasize the importance of preclinical animal models in understanding and evaluating the interaction between CMAs and the immune system and tumor matrix, which ultimately influences CMA PK (clearance and distribution) and PD (efficacy and toxicity). It is fundamental to study representative preclinical tumor models that recapitulate patients with diseases (e.g., cancer) and evaluate the interplay between CMAs and the immune system, including the mononuclear phagocyte system (MPS), chemokines, hormones, and other immune modulators. Furthermore, standard allometric scaling using body weight does not accurately predict drug clearance in humans. Future studies are warranted to better understand the complex pharmacology and interaction of CMA carriers within individual preclinical models and their biological systems, such as the MPS and tumor microenvironment, and their application to allometric scaling across species. WIREs Nanomed Nanobiotechnol 2016, 8:642–653. doi: 10.1002/wnan.1394 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
PLD PKs in plasma and tissues and profiling of CCL2 and CCL5 in nontumor bearing (NT) mice and mice‐bearing SKOV3 orthotopic ovarian cancer xenografts after administration of PLD at 6 mg/kg IV × 1 via tail vein. CCL2 (a) and CCL5 (b) concentration versus time profiles in plasma and tumors following PLD administration. Encapsulated and released doxorubicin exposure in plasma and sum total doxorubicin exposure in the liver and spleen (c). Data represents mean ± SEM. (n = 3). Plasma chemokine AUC0‐last and its association with PLD PKs in patients with EOC. Plasma encapsulated doxorubicin exposure positively correlated with CCL2 AUC (d) (p = 0.017) and CCL5 AUC (e) (p = 0.009); however, no association was observed in patients treated with PLD plus carboplatin (p = 0.05, data not shown). R2 and p‐values are calculated using linear regression followed by adjustment for multiple comparisons using Holm test. (Reprinted with permission from Ref . Copyright 2015 Elsevier Inc).
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Concentration versus time profiles of doxorubicin after administration of PLD and nonliposomal doxorubicin (NL‐doxo) at 6 mg/kg IV × 1 via tail vein in tumor (a) and liver (b) in basal‐like C3‐TAg and claudin‐low T11 breast tumor models. Sum total (encapsulated + released) samples (n = 3 mice at each time point) were obtained at 0.083, 0.5, 1, 3, 6, 24, 48, 72, and 96 h following PLD administration. P < 0.05 (AUC0–96 h in the C3‐TAg model versus AUC0–96h in the T11 model). (Reprinted with permission from Ref . Copyright 2014 American Association of Cancer Research).
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Clearance of nanoparticles and carrier‐mediated agents (CMAs) via the mononuclear phagocyte system (MPS). Small‐molecule (SM) anticancer agents undergo a standard route of metabolism and elimination, including enterohepatic recycling and removal through the kidney. CMAs, however, which are engulfed by phagocytes, are contained primarily in compartments such as the spleen, liver, and peripheral blood mononuclear cells. (Reprinted with permission from Refs . Copyright 2015 Future Medicine Ltd and 2012 John Wiley & Sons, respectively).
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Bidirectional interaction between nanoparticles and MPS. There is a growing body of evidence to indicate that factors such as age, body composition, gender, cellular function, and concomitant medications contribute to the variability in the PK/PD of CMAs in patients. All these factors operate at the level of the MPS and have the ability to up‐ or downregulate its function, thereby altering CMA clearance and AUC/exposure. This ultimately leads to either reduced or greater efficacy and/or toxicity. The predicament of this clinical manifestation lies in the fact that the target response must balance efficacy and toxicity, and this ideal CMA exposure needs to be elucidated through further research and determination of proper preclinical model(s).
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Relationship between phagocytosis (a) and production of ROS (b) in MO from blood and clearance of PEGylated liposomal agents in mice, rats, dogs, and patients. The ability to translate results of CMA preclinical data to human patients may require measuring cellular function of the cells responsible for CMA uptake and clearance. The mean values for three species are represented by individual symbols, with diamonds as PLD, squares as S‐CKD602, and triangles as SPI‐077. The species data are in vertical columns from left to right: rats, mice, dogs, and patients. The best fit line for each group is represented by the solid lines. Across species, a positive association was observed between cell function and clearance of PEGylated liposomes. (Reprinted with permission from Ref . Copyright 2004 ASPET).
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Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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