Carrier-mediated Agents Research Articles

Methods and Study Designs for Characterizing the Pharmacokinetics and Pharmacodynamics of Carrier-Mediated Agents.

Major advances in carrier-mediated agents (CMAs), 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. In this chapter, we focus on the analytical and phenotypic methods required to design a study that characterizes the pharmacokinetics (PK) and pharmacodynamics (PD) of all forms of these nanoparticle-based drug agents. These methods include separation of encapsulated and released drugs, ultrafiltration for measurement of non-protein bound active drug, microdialysis to measure intra-tumor drug concentrations, immunomagnetic separation and flow cytometry for sorting cell types, and evaluation of spatial distribution of drug forms relative to tissue architecture by mass spectrometry imaging and immunohistochemistry.

Pharmacokinetics and efficacy of doxorubicin-loaded plant virus nanoparticles in preclinical models of cancer.

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. 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. 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. PVNs administered at lower repeated doses provide both pharmacologic and efficacy advantages compared with PLD.

Complex effects of tumor microenvironment on the tumor disposition of carrier-mediated agents.

Major advances in carrier-mediated agents, including nanoparticle, conjugates and antibody-drug conjugates, have created revolutionary drug delivery systems in cancer over the past two decades. While these agents provide several advantages, such as greater duration of exposure and solubility, compared with their small-molecule counterparts, there is substantial variability in delivery of these agents to tissues and especially tumors. This review provides an overview of tumor microenvironment factors that affect the pharmacokinetics and pharmacodynamics of carrier-mediated agents observed in preclinical models and patients.

Meta-analysis of clinical and preclinical studies comparing the anticancer efficacy of liposomal versus conventional non-liposomal doxorubicin

While liposome-mediated delivery of cytotoxic chemotherapy has been shown to significantly enhance drug tolerability in patients as compared to the conventional formulation, the fundamental question remains whether they also improve anticancer efficacy. Thus, we performed a systematic literature search for randomized clinical trials directly comparing efficacy of liposomal cytotoxic chemotherapy versus their equivalent conventional formulation. The search yielded 14 clinical trials (8 anthracycline, 4 cisplatin, 1 paclitaxel, 1 irinotecan) that meet inclusion criteria, with a total of 2589 patients. We found that efficacy in patients was not different between liposomal and conventional chemotherapy as assessed by objective response (odds ratio 1.03; 95% confidence interval [CI] 0.82–1.30), overall survival (hazard ratio [HR] 1.05; 95% CI 0.95–1.17), and progression free survival rates (HR 1.01; 95% CI, 0.92–1.11). Subgroup analyses of only the anthracycline trials also did not show any efficacy advantage for the liposomal formulation. Since pegylated liposomal doxorubicin (PLD) was the most prevalent formulation in these clinical trials, we also performed a meta-analysis of 11 preclinical studies comparing efficacy of PLD and conventional doxorubicin in tumor-bearing mice. In contrast with clinical results, animal studies showed significantly increased survival in mice treated with PLD compared to conventional doxorubicin (HR 0.39; 95% CI 0.27–0.56). We discuss the possible reasons why the pharmacological advantages of carrier-mediated chemotherapy did not translate into enhanced clinical efficacy including the role of the enhanced permeability and retention (EPR) effect and the tumor microenvironment, the optimal dosing regimen for carrier-mediated agents, and the lack of standardization in the conduct and reporting of preclinical studies evaluating anticancer efficacy of these agents. Our study shows that the full clinical potential of carrier-mediated drugs remains to be realized and highlights some of the critical knowledge gaps that must be addressed in order to move the field forward.

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.

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

Abstract 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. <10-20%). Thus, there is a need to discover methods of improving the overall delivery of CMAs to tumors. Microbeam radiation therapy (MRT) is a novel radiation therapy treatment that has been shown to eradicate tumor without damaging the function of normal tissues exposed to the same high dose radiation in animal studies. MRT utilizes an array of parallel microplaner beams delivering periodically oscillating high and low dose regions in the treatment volume. Our preliminary results suggest that MRT alters tumor microvasculature differently than normal tissue microvasculature. We hypothesize that the changes in microvasculature induced by MRT can be used to enhance drug delivery to tumors. Thus, we evaluated the effects of MRT on the pharmacokinetics (PK) of PEGylated liposomal doxorubicin (PLD) in preclinical tumor models. 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 MRT's 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

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.

Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT).

The pharmacokinetics (PK) of carrier-mediated agents (CMA) is dependent upon the carrier system. As a result, CMA PK differs greatly from the PK of small molecule (SM) drugs. Advantages of CMAs over SMs include prolonged circulation time in plasma, increased delivery to tumors, increased antitumor response, and decreased toxicity. In theory, CMAs provide greater tumor drug delivery than SMs due to their prolonged plasma circulation time. We sought to create a novel PK metric to evaluate the efficiency of tumor and tissue delivery of CMAs and SMs. We conducted a study evaluating the plasma, tumor, liver, and spleen PK of CMAs and SMs in mice bearing subcutaneous flank tumors using standard PK parameters and a novel PK metric entitled relative distribution over time (RDI-OT), which measures efficiency of delivery. RDI-OT is defined as the ratio of tissue drug concentration to plasma drug concentration at each time point. The standard concentration versus time area under the curve values (AUC) of CMAs were higher in all tissues and plasma compared with SMs. However, 8 of 17 SMs had greater tumor RDI-OT AUC0-last values than their CMA comparators and all SMs had greater tumor RDI-OT AUC0-6 h values than their CMA comparators. Our results indicate that in mice bearing flank tumor xenografts, SMs distribute into tumor more efficiently than CMAs. Further research in additional tumor models that may more closely resemble tumors seen in patients is needed to determine if our results are consistent in different model systems.

Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT)

Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT)

A Review of Study Designs and Outcomes of Phase I Clinical Studies of Nanoparticle Agents Compared with Small-Molecule Anticancer Agents

Nanoparticles or carrier-mediated agents have been designed to prolong drug circulation time, increase tumor delivery, and improve therapeutic index compared to their small-molecule counterparts. The starting dose for phase I studies of small molecules and nanoparticles anticancer agents is based on the toxicity profile of the most sensitive species (e.g., rat or canine), but the optimal animal model for these studies of nanoparticles is unclear. The objective of this study was to evaluate the design, progression, and outcomes of phase I studies of nanoparticles compared with small-molecule anticancer agents. In preclinical studies, the maximum tolerated dose (MTD) in rats and dogs was evaluated for nanoparticles and their respective small molecules. In phase I clinical trials in patients with advanced solid tumors, the basis for starting dose, the number of dose escalations, number of patients enrolled, and the ratio of MTD to starting dose was determined for nanoparticles and small molecules. The mean ratio of MTD to starting dose in clinical phase I studies was significantly greater for nanoparticles (13.9 ± 10.8) compared with small molecules (2.1 ± 1.1; P = 0.005). The number of dose levels in a clinical phase I study was also significantly greater for nanoparticles (7.3 ± 2.9) compared with small molecules (4.1 ± 1.5; P = 0.008). The degree of dose escalation from starting dose to MTD was significantly greater for nanoparticles as compared with small-molecule anticancer drugs. These findings necessitate the need to identify the most appropriate preclinical animal model to use when evaluating nanoparticles toxicity.

Abstract 3355: Evaluation of the efficiency of tumor and tissue delivery of carrier mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric relative distribution index over time (RDI-OT).

Abstract Background: The PK of CMA are dependent upon the carrier system. As a result, CMA PK differ greatly from the PK of SM drugs. Advantages of CMA included prolonged circulation time in plasma, increased delivery to tumors which results in increased antitumor response and decreased toxicity. In theory, the prolonged circulation time of CMA in plasma is thought to result in greater tumor delivery compared with SM. We conducted a meta-analysis evaluating the plasma, tumor, liver, and spleen PK of CMA and SM using standard PK parameters and a novel PK metric RDI-OT which measures efficiency of delivery. Methods: A literature search identified PK studies of CMA (n=17) and comparative SM (n=15) in plasma, tumor, liver and spleen of mice bearing synergistic and xenograft subcutaneous tumors. The area under the concentration versus time curves (AUC) were calculated. This data was also used to calculate a novel PK metric, RDI-OT. RDI-OT is defined as [Drug]tissue/[Drug]plasma at each time point. RDI-OT versus time plots were generated and the area under the curve (RDI-OT AUC) was calculated from 0 h to 24 h and last time point. Results: The table below summarizes the mean + SD and range of standard PK parameters and RDI-OT for CMA and SM. Summary of pharmacokinetic properties by agent type Agent Type CMA SM Mean + SD Range Mean + SD Range AUCplasma (mcg/ml*h) 8,113.7 + 21,620.6 10.5–90,889.6 18.2 + 33.7 0.5–133.8 AUCtumor (mcg/ml*h) 3,605.2 + 8,790.1 13.2–35,400.5 83.8 + 94.4 0.8–243.0 AUCtumor/AUCplasma 1.0 + 1.3 0.04–4.8 8.2 + 11.0 0.3–38.6 SM AUCtumor: AUCplasma 40.6 + 112.3 473.1–0.7 CMA AUCtumor: AUCplasma RDI-OTtumor AUC0-Last 46,289.3 + 179,143.8 3.0–741,095.9 1565.0 + 3053.6 0.8–11057.7 SM RDI-OTtumor AUC 1.7 + 3.1 0.00009–13.4 CMA RDI-OTtumor AUC RDI-OTtumor AUC0-24h 15.4 + 37.1 0.1–121.8 43.4 + 96.8 0.01–361.8 SM RDI-OTtumor AUC0-24h 30.5 + 78.2 0.1–319.2 CMA RDI-OTtumor AUC0-24h Conclusions: RDI-OT is a novel metric for assessing the efficiency of drug distribution into tumors and tissues. Our results indicate that in mice bearing flank tumor xenografts SM distribute into tumor more efficiently than CMA. The lower efficiency of delivery seen in CMA compared with SM suggests there may be a limit to CMA entry into flank tumors in mice. Further research in additional tumor models that may more closely resemble tumors seen in patients is needed to determine if our results are consistent in different model systems. Citation Format: Andrew J. Madden, Sumit Rawal, Kevin Chu, Katie Sandison, Ryan Schell, Lan Feng, Ping Ma, Russell Mumper, Joseph DeSimone, William C. Zamboni. Evaluation of the efficiency of tumor and tissue delivery of carrier mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric relative distribution index over time (RDI-OT). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3355. doi:10.1158/1538-7445.AM2013-3355

Interpatient Pharmacokinetic and Pharmacodynamic Variability of Carrier-Mediated Anticancer Agents

Major advances in the field of carrier-mediated agents (CMAs) have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages over their small-molecule counterparts (solubility,duration of exposure, and delivery to the site of action are higher), these agents display substantial variability in systemic clearance (CL) and distribution, tumor delivery, and pharmacologic effects. This review provides an overview of factors that affect the pharmacokinetics (PK) and pharmacodynamics (PD) of CMAs in preclinical models and patients.

Abstract 371: Comparison of toxicity and study design issues of nanoparticle and small molecule anticancer agents in preclinical models and phase I clinical trials

Abstract Background: Carrier-mediated agents (CMA) are classified as nanoparticles, nanosomes (nanoparticle sized liposomes) and conjugates. Anticancer CMA offer many unique advantages over their traditional small molecule (SM) counterparts, including improved solubility, longer duration of exposure, tumor-selective delivery, increased antitumor response and reduced toxicity. The interpatient variability in pharmacokinetics (PK) and pharmacodynamics (PD) associated with nanoparticles are greater than that observed with SM. The starting dose for phase I studies of SM and CMA anticancer agents is based on the toxicity profile of the most sensitive species (e.g. rat or canine). However, the optimal animal model for toxicologic and pharmacologic studies of CMA is unclear. Our preliminary data suggests that dogs are highly sensitive to nanoparticles and thus may not be an appropriate animal model in determining the starting dose of CMA for phase I clinical trials. We evaluated preclinical toxicology data and how this affected the design and progression of phase I studies of CMA compared to SM anticancer agents. Methods: In preclinical studies, the maximum tolerated dose (MTD) in rats and dogs was evaluated for CMA and their respective SM. In phase I clinical trials of CMA and their respective SM in patients with advanced solid tumors, the basis for starting dose, the number of dose escalations, number of patients and the ratio of MTD to starting dose was determined. Results: Starting dose in phase I studies of CMA was based on dogs. Conclusions: The degree of dose escalation from starting dose to MTD was significantly greater for CMA compared to SM drugs. This was also associated with a significantly greater number of dose levels, patients, and time required to complete phase I studies of CMA compared to SM. These findings necessitate the need to identify the most appropriate preclinical animal model to use to evaluate CMA toxicity in phase I studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 371. doi:10.1158/1538-7445.AM2011-371

Concept and Clinical Evaluation of Carrier-Mediated Anticancer Agents

Major advances in the use of carrier vehicles delivering pharmacologic agents and enzymes to sites of disease have occurred over the past 10 years. This review focuses on the concepts and clinical evaluation of carrier-mediated anticancer agents that are administered i.v. or orally. The primary types of carrier-mediated anticancer agents are nanoparticles, nanosomes, which are nanoparticle-sized liposomes, and conjugated agents. Nanosomes are further subdivided into stabilized and nonstabilized or conventional nanosomes. Nanospheres and dendrimers are subclasses of nanoparticles. Conjugated agents consist of polymer-linked and pegylated agents. The theoretical advantages of carrier-mediated drugs are greater solubility, longer duration of exposure, selective delivery of entrapped drug to the site of action, superior therapeutic index, and the potential to overcome resistance associated with the regular anticancer agent. The pharmacokinetic disposition of carrier-mediated agents depends on the physiochemical characteristics of the carrier, such as size, surface charge, membrane lipid packing, steric stabilization, dose, and route of administration. The primary sites of accumulation of carrier-mediated agents are the tumor, liver, and spleen, compared with noncarrier formulations. The drug that remains encapsulated in or linked to the carrier (e.g., the nanosome or nanoparticle) is an inactive prodrug, and thus the drug must be released from the carrier to be active. The factors affecting the pharmacokinetic and pharmacodynamic variability of these agents remain unclear, but most likely include the reticuloendothelial system, which has also been called the mononuclear phagocyte system. Future studies need to evaluate the mechanism of clearance of carrier-mediated agents and identify the factors associated with the pharmacokinetic and pharmacodynamic variability of carrier agents in patients and specifically in tumors.