Profiling the relationship between tumor-associated macrophages and pharmacokinetics of liposomal agents in preclinical murine models

Lucas, Andrew T.; White, T.; Deal, Allison M.; Herity, Leah B.; Song, Gina; Santos, Charlene; Zamboni, William C.

doi:10.1016/j.nano.2016.09.015

Cited by 15 publications

(17 citation statements)

References 40 publications

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“…Currently, nanomedicines such as liposomal formulation have become a successful drug delivery system in clinics for their capabilities of altering the behaviors of chemotherapeutics in vivo and reducing their toxicity on normal tissues. 2 …”

Section: Introductionmentioning

confidence: 99%

In vivo study of doxorubicin-loaded cell-penetrating peptide-modified pH-sensitive liposomes: biocompatibility, bio-distribution, and pharmacodynamics in BALB/c nude mice bearing human breast tumors

Ding¹,

Cui²,

Shen³

et al. 2017

DDDT

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In vivo evaluation of drug delivery vectors is essential for clinical translation. In BALB/c nude mice bearing human breast cancer tumors, we investigated the biocompatibility, pharmacokinetics, and pharmacodynamics of doxorubicin (DOX)-loaded novel cell-penetrating peptide (CPP)-modified pH-sensitive liposomes (CPPL) (referred to as CPPL(DOX)) with an optimal CPP density of 4%. In CPPL, a polyethylene glycol (PEG) derivative formed by conjugating PEG with stearate via acid-degradable hydrazone bond (PEG2000-Hz-stearate) was inserted into the surface of liposomes, and CPP was directly attached to liposome surfaces via coupling with stearate to simultaneously achieve long circulation time in blood and improve the selectivity and efficacy of CPP for tumor targeting. Compared to PEGylated liposomes, CPPL enhanced DOX accumulation in tumors up to 1.9-fold (p<0.01) and resulted in more cell apoptosis as a result of DNA disruption as well as a relatively lower tumor growth ratio (T/C%). Histological examination did not show any signs of necrosis or inflammation in normal tissues, but large cell dissolving areas were found in tumors following the treatment of animals with CPPL(DOX). Our findings provide important and detailed information regarding the distribution of CPPL(DOX) in vivo and reveal their abilities of tumor penetration and potential for the treatment of breast cancer.

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Section: Introductionmentioning

confidence: 99%

In vivo study of doxorubicin-loaded cell-penetrating peptide-modified pH-sensitive liposomes: biocompatibility, bio-distribution, and pharmacodynamics in BALB/c nude mice bearing human breast tumors

Ding¹,

Cui²,

Shen³

et al. 2017

DDDT

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show abstract

“…These results suggest the close relationship between nanoparticle delivery and the MPS. More recently, the same group confirmed the importance of tumor microenvironment heterogeneity depending on tumor type, by profiling the MPS in mice bearing ovarian, breast, and endometrial xenografts[56].Macrophages were quantified in the liver, the spleen and the tumor and marked differences were found between the tumor types. Significantly more macrophages were found in both liver and spleen in animals with endometrial cancer than those with breast and ovarian cancers.…”

mentioning

confidence: 83%

Pharmacokinetics variability: Why nanoparticles are not just magic-bullets in oncology

Rodallec

Benzekry

Lacarelle

et al. 2018

Critical Reviews in Oncology/Hematology

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Developing nanoparticles to improve the specificity of anticancer agents towards tumor tissue and to better control drug delivery is a rising strategy in oncology. An increasing number of forms (e.g., conjugated nanoparticles, liposomes, immunoliposomes…) are now available on the shelves and numerous other scaffolds (e.g., dendrimeres, nanospheres, squalenes …) are currently at various stages of development. However, as of today most nanoparticles made available remain lipidic carriers. Pharmacokinetic variability is a major, yet largely underestimated issue with liposomal nanoparticles. A wide variety of causes (e.g., tumor type and disease staging, comorbidities, patient's immune system) can explain this variability, which can in return negatively impact pharmacodynamic endpoints such as poor efficacy or severe toxicities. This review aims to cover the main causes for erratic pharmacokinetics observed with most nanoparticles, especially liposomes used in oncology. Should the main causes of such variability be identified, specific studies in non-clinical or clinical development stages could be undertaken using dedicated models (i.e., mechanistic or semi-mechanistic mathematical models such as PBPK approaches) to better describe nanoparticles pharmacokinetics and decipher PK/PD relationships. In addition, identifying relevant biomarkers or parameters likely to impact nanoparticles pharmacokinetics would allow for either the modification of their characteristics to reduce the influence of the expected variability during development phases or the development of biomarker-based adaptive dosing strategies to maintain an optimal efficacy/toxicity balance. Broadly, we call for the development of comprehensive distribution studies and state-of-the-art modeling support to better understand and anticipate nanoparticle pharmacokinetics in oncology.

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“…81–84 Moreover, in tumor-bearing mice, tumor accumulation and the antitumor activity of liposomal drugs have been associated with the presence of phagocytic cells in tumors. 85 The phagocytic cells in xenograft tumors have been found to be responsible for the metabolism and subsequent drug release of nanoparticles. 85 PEGylated liposomal CKD602 has higher clearance in patients with liver tumor metastasis, which is the opposite for small molecules.…”

Section: Disposition Of Nanoparticlesmentioning

confidence: 99%

“…85 The phagocytic cells in xenograft tumors have been found to be responsible for the metabolism and subsequent drug release of nanoparticles. 85 PEGylated liposomal CKD602 has higher clearance in patients with liver tumor metastasis, which is the opposite for small molecules. 81 The unexpected higher clearance of nanoparticles in patients with tumor metastasis could be explained by more activated macrophages in the liver triggered by local inflammation.…”

Section: Disposition Of Nanoparticlesmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling of Nanoparticles

Yuan

et al. 2019

Journal of Pharmaceutical Sciences

119

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Nanoparticles are frequently designed to improve the pharmacokinetics profiles and tissue distribution of small molecules in order to prolong their systemic circulation, target specific tissue, or widen the therapeutic window. The multi-functionality of nanoparticles is frequently presented as an advantage but also results in distinct and complicated in vivo disposition properties compared to a conventional formulation of the same molecules. Physiologically-based pharmacokinetic (PBPK) modeling has been a useful tool in characterizing and predicting the systemic disposition, target exposure, and efficacy/toxicity of various types of drugs when coupled with pharmacodynamics (PD) modeling. Here, we review the unique disposition characteristics of nanoparticles, assess how PBPK modeling takes into account the unique disposition properties of nanoparticles, and comment on the applications and challenges of PBPK modeling in characterizing and predicting the disposition and biological effects of nanoparticles.

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Profiling the relationship between tumor-associated macrophages and pharmacokinetics of liposomal agents in preclinical murine models

Cited by 15 publications

References 40 publications

In vivo study of doxorubicin-loaded cell-penetrating peptide-modified pH-sensitive liposomes: biocompatibility, bio-distribution, and pharmacodynamics in BALB/c nude mice bearing human breast tumors

In vivo study of doxorubicin-loaded cell-penetrating peptide-modified pH-sensitive liposomes: biocompatibility, bio-distribution, and pharmacodynamics in BALB/c nude mice bearing human breast tumors

Pharmacokinetics variability: Why nanoparticles are not just magic-bullets in oncology

Physiologically Based Pharmacokinetic Modeling of Nanoparticles

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