Andrew J. Madden

Nanoparticles and the Mononuclear Phagocyte System: Pharmacokinetics and Applications for Inflammatory Diseases

Nanoparticles (NPs) provide several advantages over the small molecule drugs including prolonged circulation time and enhanced delivery to targeted sites. Once a NP enters the body, it interacts with hosts immune system and is engulfed by cells of the mononuclear phagocyte system (MPS). The interaction between NPs and the immune cells can result in immunosuppression or immunostimulation, which may enhance or reduce the treatment effects of NPs. Therefore, it is critical to understand the interactions between NPs and the immune system in order to optimize the treatment benefit and minimize the undesirable toxicities of NPs. This review elaborates on the interaction between NP and the MPS and its impacts on the pharmacokinetics (PK) and pharmacodynamics (PD) of NPs and applications for inflammatory diseases. This review also encompasses an overview of NPs being developed for treatment of inflammatory diseases.

The effects of nanoparticle drug loading on the pharmacokinetics of anticancer agents

Major advances in carrier-mediated agents, which include nanoparticles, nanosomes and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages, such as greater solubility, duration of exposure and delivery to the site of action over their small-molecule counterparts, there is substantial variability in systemic clearance and distribution, tumor delivery and pharmacologic effects (efficacy and toxicity) of these agents. This review provides an overview of factors that affect the pharmacokinetics and pharmacodynamics of carrier-mediated agents in preclinical models and patients.

Formulation and physiologic factors affecting the pharmacology of carrier-mediated anticancer agents

Introduction: 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 such as increased exposure duration, greater solubility and delivery to tumor sites over their small molecule counterparts, there is substantial variability in how individual CMA formulations affect the pharmacology, pharmacokinetics and pharmacodynamics (efficacy and toxicity) of these agents. Areas covered: CMA formulations are complex in nature compared to their small molecule counterparts and consist of multiple components and variables that can affect the pharmacological profile. This review provides an overview of factors that affect the pharmacologic profiles observed in CMA-formulated chemotherapy, primarily in liposomal formulations, that are currently in preclinical or early clinical development. Expert opinion: Despite the numerous advantages that CMA formulations provide, their clinical use is still in its infancy. It is critical that we understand the mechanisms and effects of CMAs in navigating biological barriers and how these factors affect their biodistribution and delivery to tumors. Future studies are warranted to better understand the complex pharmacology and interaction between CMA carriers and biological systems, such as the mononuclear phagocyte system and tumor microenvironment.

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

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 For further resources related to this article, please visit the WIREs website.

2'-(2-bromohexadecanoyl)-paclitaxel conjugate nanoparticles for the treatment of non-small cell lung cancer in an orthotopic xenograft mouse model

A nanoparticle (NP) formulation with 2′-(2-bromohexadecanoyl)-paclitaxel (Br-16-PX) conjugate was developed in these studies for the treatment of non-small cell lung cancer (NSCLC). The lipophilic paclitaxel conjugate Br-C16-PX was synthesized and incorporated into lipid NPs where the 16-carbon chain enhanced drug entrapment in the drug delivery system and improved in vivo pharmacokinetics. The electron-withdrawing bromine group was used to facilitate the conversion of Br-C16-PX to paclitaxel at the tumor site. The developed system was evaluated in luciferase-expressing A549 cells in vitro and in an orthotopic NSCLC mouse model. The results demonstrated that the Br-C16-PX NPs had a higher maximum tolerated dose (75 mg/kg) than Taxol® (19 mg/kg) and provided significantly longer median survival (88 days versus 70 days, P<0.05) in the orthotopic NSCLC model. An improved pharmacokinetic profile was observed for the Br-C16-PX NPs at 75 mg/kg compared to Taxol at 19 mg/kg. The area under the concentration versus time curve (AUC)0–96 h of Br-C16-PX from the NPs was 91.7-fold and 49.6-fold greater than Taxol in plasma and tumor-bearing lungs, respectively, which provided sustained drug exposure and higher antitumor efficacy in the NP-treated group.

Pharmacokinetic and screening studies of the interaction between mononuclear phagocyte system and nanoparticle formulations and colloid forming drugs

Studies have shown that nanoparticles (NPs) are cleared through the mononuclear phagocyte system (MPS). Pharmacokinetic studies of Doxil, DaunoXome, micellar doxorubicin (SP1049C) and small molecule (SM) doxorubicin were performed in SCID mice, Sprague-Dawley rats, and beagle dogs. An ex vivo MPS profiling platform was used to evaluate the interaction between the same agents, as well as colloid-forming and non-colloid forming SM drugs. In all species, the systemic clearance was highest for SP1049C and lowest for Doxil. With the exception of dog blood, the MPS screening results of mouse and rat blood showed that the greatest reduction in phagocytosis occurred after the ex vivo addition of SM-doxorubicin>SP1049C>DaunoXome>Doxil. The MPS profiling platform in rats, but not dogs, could differentiate between colloid forming and non-colloid forming drugs. The results of the MPS profiling platform were generally consistent with in vivo clearance rates of NP and SM anticancer drugs in mice and rats. This study suggests the MPS profiling platform is an effective method to screen and differentiate the important characteristics of NPs and colloid-forming drugs that affect their in vivo clearance. Implications of these findings on preclinical prediction of human clearance are discussed.

Pharmacokinetics and efficacy of doxorubicin-loaded plant virus nanoparticles in preclinical models of cancer: Nanomedicine (Lond)

AIM To compare the pharmacokinetics and efficacy of doxorubicin containing plant virus nanoparticles (PVNs) with PEGylated liposomal doxorubicin (PLD) and small molecule doxorubicin in two mouse models of cancer. MATERIALS & METHODS Studies were performed in A375 melanoma and intraperitoneal SKOV3ip1 ovarian cancer xenografts. The PVNs were administered in lower and more frequent doses in the ovarian model. RESULTS The PVNs were more efficacious than PLD and small molecule doxorubicin in the ovarian cancer model, but not in the melanoma cancer model. The pharmacokinetics profiles of the PVNs showed fast plasma clearance, but more efficient tumor delivery as compared with other carrier-mediated agents. CONCLUSION PVNs administered at lower repeated doses provide both pharmacologic and efficacy advantages compared with PLD.

Abstract 4516: The effects of microbeam radiation therapy on the pharmacokinetics of PEGylated liposomal doxorubicin in a triple negative breast cancer GEM model

Background: Carrier-mediated agents (CMAs), such as nanoparticle and liposomes, can achieve greater exposure in tumors compared with small molecule drugs; however, the overall percent of CMAs that distribute from the plasma to tumor is relatively low (e.g. Methods: Studies were performed in mice bearing p53 null syngeneic orthotopic tumor transplants. This model, named “T11”, has been characterized by gene expression array to reflect the claudin-low subtype of triple-negative breast cancer. Prior to administration of PLD, mice received a single treatment of 28Gy or 34Gy (peak dose at skin entrance) MRT to the tumor site (treatment area is ∼1cm x 1cm), or no radiation treatment. All groups were then administered PLD at 6 mg/kg IV x 1 at 16 h after MRT. Mice (n = 3) were sacrificed at 5 min, 6 h, and 24 h after PLD. Mice treated with 34 Gy MRT were only sacrificed at 24 h after PLD. The PK of PLD in plasma and tumor was evaluated. Results: Mice treated with 28 Gy MRT prior to PLD administration and PLD alone had a total doxorubicin tumor AUC of 206,040.0 ng/mL•h and 55,506.5 ng/mL•h, respectively. After treatment with 28 Gy and 34 Gy MRT the concentration of total doxorubicin in tumor at 24 h after administration of PLD were 10,665.8 ng/ml and 20,779.0 ng/ml, respectively. The plasma PK of PLD was similar in all groups. Conclusions: MRT treatment prior to PLD administration significantly improves the delivery of PLD to tumors without altering the plasma PK. In addition, higher doses of MRT resulted in a greater increase in the delivery of PLD to tumors. The improved delivery of PLD to tumors may be due to MRT9s acute effects on tumor microvasculature; however, the exact mechanism needs to be further evaluated. Future studies include evaluation of the effect of duration and dose of MRT on drug uptake in tumor, effects of MRT on other CMAs, and the mechanisms of enhanced tumor delivery. Citation Format: Xiao S. Chang, Andrew Jacob Madden, Judith Rivera, Charlene Santos, David Darr, Lucas Hunter, William C. Zamboni. The effects of microbeam radiation therapy on the pharmacokinetics of PEGylated liposomal doxorubicin in a triple negative breast cancer GEM model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4516. doi:10.1158/1538-7445.AM2015-4516