From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer

Rodallec, Anne; Sicard, Guillaume; Giacometti, Sarah; Carré, Manon; Pourroy, Bertrand; Bouquet, Fanny; Savina, Ariel; Lacarelle, Bruno; Ciccolini, Joseph; Fanciullino, Raphaëlle

doi:10.2147/ijn.s179290

Cited by 31 publications

(35 citation statements)

References 27 publications

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“…Animal tumor model studies were performed in strict accordance with guidelines for animal welfare in experimental oncology and were approved by local ethics committees. Precise description of experimental protocols was reported elsewhere (see [15] for the volume measurements and [25] for the fluorescence measurements).…”

Section: Mice Experimentsmentioning

confidence: 99%

A reduced Gompertz model for predicting tumor age using a population approach

Vaghi

Rodallec

Fanciullino

et al. 2019

Preprint

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Tumor growth curves are classically modeled by ordinary differential equations. In analyzing the Gompertz model several studies have reported a striking correlation between the two parameters of the model.We analyzed tumor growth kinetics within the statistical framework of nonlinear mixed-effects (population approach). This allowed for the simultaneous modeling of tumor dynamics and interanimal variability. Experimental data comprised three animal models of breast and lung cancers, with 843 measurements in 94 animals. Candidate models of tumor growth included the Exponential, Logistic and Gompertz. The Exponential and -more notably -Logistic models failed to describe the experimental data whereas the Gompertz model generated very good fits. The population-level correlation between the Gompertz parameters was further confirmed in our analysis (R 2 > 0.96 in all groups). Combining this structural correlation with rigorous population parameter estimation, we propose a novel reduced Gompertz function consisting of a single individual parameter. Leveraging the population approach using bayesian inference, we estimated the time of tumor initiation using three late measurement timepoints. The reduced Gompertz model was found to exhibit the best results, with drastic improvements when using bayesian inference as compared to likelihood maximization alone, for both accuracy and precision. Specifically, mean accuracy was 12.1% versus 74.1% and mean precision was 15.2 days versus 186 days, for the breast cancer cell line.These results offer promising clinical perspectives for the personalized prediction of tumor age from limited data at diagnosis. In turn, such predictions could be helpful for assessing the extent of invisible metastasis at the time of diagnosis. Author summaryMathematical models for tumor growth kinetics have been widely used since several decades but mostly fitted to individual or average growth curves. Here we compared three classical models (Exponential, Logistic and Gompertz) using a population approach, which accounts for inter-animal variability. The Exponential and the Logistic models failed to fit the experimental data while the Gompertz model showed excellent descriptive power. Moreover, the strong correlation between the two parameters of the Gompertz equation motivated a simplification of the model, the reduced Gompertz model, with a single individual parameter and equal descriptive power. Combining the mixed-effects approach with Bayesian inference, we predicted the age of individual tumors with only few late measurements. Thanks to its simplicity, the reduced Gompertz model showed superior predictive power. Although our method remains to be extended to clinical data, these results are promising for the personalized estimation of the age of a tumor from limited measurements at diagnosis. Such predictions could contribute to the development of computational models for metastasis.

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Section: Mice Experimentsmentioning

confidence: 99%

A reduced Gompertz model for predicting tumor age using a population approach

Vaghi

Rodallec

Fanciullino

et al. 2019

Preprint

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“…The three batches of immunoliposomes were then tested in vitro on bidimensional (2D) and three-dimensional (3D) models. We found that similarly to standard MTT assays 26,34 , apoptosis studies using 2D models were not suitable to discriminate the efficacy of the various immunoliposomes as compared with free docetaxel or liposomal docetaxel. Conversely when using 3D spheroids, we found that all immunoliposomes performed better than free docetaxel and its liposomal form.…”

Section: Discussionmentioning

confidence: 82%

“…In vitro efficacy studies: three-dimensional (3D) model. Empty liposomes and trastuzumab alone did not show cytotoxic effect on MDA-MB-453 (data not shown) 26 . Spheroid monitoring is summarized in Fig.…”

Section: Detection Of Immunoliposomes and Quantification Of Coated Trmentioning

confidence: 88%

“…immunoliposomes. Here, we worked on prototyping docetaxel-trastuzumab immunoliposome which previously demonstrated in vitro 7 and in vivo 26 anti-tumor efficacy. However, two major hurdles had to be overcome: first, QFCM had never been applied yet on submicrometer-sized particles and second, FCM analysis of nanoparticles was still a major challenge 27 .…”

Section: Discussionmentioning

confidence: 99%

“…Thus, Immunoliposome-2, corresponding to 480 ± 110 molecules of coated trastuzumab per liposome, could be the optimal number of trastuzumab to be coated to ensure a maximal efficacy in this breast cancer model. Interestingly, preliminary in vivo efficacy studies have already shown its benefit over free docetaxel + free trastuzumab and antibody drug conjugate T-DM1 26 .…”

Section: Discussionmentioning

confidence: 99%

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Prototyping Trastuzumab Docetaxel Immunoliposomes with a New FCM-Based Method to Quantify Optimal Antibody Density on Nanoparticles

Rodallec¹,

Franco²,

Robert³

et al. 2020

Sci Rep

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Developing targeted nanoparticles is a rising strategy to improve drug delivery in oncology. Antibodies are the most commonly used targeting agents. However, determination of their optimal number at the surface remains a challenging issue, mainly due to the difficulties in measuring precisely surface coating levels when prototyping nanoparticles. We developed an original quantitative assay to measure the exact number of coated antibodies per nanoparticle. Using flow cytometry optimized for submicron particle analysis and beads covered with known amounts of human igG-kappa mimicking various amounts of antibodies, this new method was tested as part of the prototyping of docetaxel liposomes coated with trastuzumab against Her2+ breast cancer. This quantification method allowed to discriminate various batches of immunoliposomes depending on their trastuzumab density on nanoparticle surface (i.e., 330 (Immunoliposome-1), 480 (Immunoliposome-2) and 690 (Immunoliposome-3), p = 0.004, One-way ANOVA). Here we showed that optimal number of grafted antibodies on nanoparticles should be finely tuned and highest density of targeting agent is not necessarily associated with highest efficacy. Overall, this new method should help to better prototype third generation nanoparticles. Development of nanoparticles (NP) for targeted delivery and controlled drug release may improve the therapeutic index of drugs, especially that of anticancer agents. Such improvement is particularly relevant when administering cytotoxics that show frequently dose-limiting toxicities, thus resulting in suboptimal efficacy 1. In addition to passive targeting through the Enhanced Permeation and Retention effect 2,3 , active targeting is based upon receptor-mediated binding of nanoparticles to the membrane of tumor cells. A successful and actively targeted nanomedicine requires therefore a fine balance of ligand content and surface exposure of cell-binding moieties that minimize immunological recognition and rapid clearance by macrophages and scavenging cells. The current methods for post-synthesis NP surface modification often require multi-steps complicated procedures, thus making difficult to achieve batch-to-batch reproducibility 4-6. This calls for the need to develop post-synthesis analytical methods to control the surface properties of the NP, such as the exact coating rate when a monoclonal antibody is to be used as a targeting agent. To date, no such method has been made available and little information is usually provided regarding the exact number of monoclonal antibodies coated on third generation nanoparticles such as immunoliposomes. Assaying monoclonal antibodies in pharmaceutical preparations is mostly based upon Enzyme Linked ImmunoSorbent Assay (ELISA) techniques. Indirect methods such as Bradford assay or Pierce BCA protein assay have been proposed, but they can only provide semi-quantitative information and are in no way suitable to precisely measure the exact amount of antibodies grafted on a nanoparticle surface 7-10. Flow

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Liposomes and Extracellular Vesicles as Drug Delivery Systems: A Comparison of Composition, Pharmacokinetics, and Functionalization

Koog

Gandek

Nagelkerke

2021

Adv Healthcare Materials

195

116

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Over the past decades, lipid-based nanoparticle drug delivery systems (DDS) have caught the attention of researchers worldwide, encouraging the field to rapidly develop improved ways for effective drug delivery. One of the most prominent examples is liposomes, which are spherical shaped artificial vesicles composed of lipid bilayers and able to encapsulate both hydrophilic and hydrophobic materials. At the same time, biological nanoparticles naturally secreted by cells, called extracellular vesicles (EVs), have emerged as promising more complex biocompatible DDS. In this review paper, the differences and similarities in the composition of both vesicles are evaluated, and critical mediators that affect their pharmacokinetics are elucidate. Different strategies that have been assessed to tweak the pharmacokinetics of both liposomes and EVs are explored, detailing the effects on circulation time, targeting capacity, and cytoplasmic delivery of therapeutic cargo. Finally, whether a hybrid system, consisting of a combination of only the critical constituents of both vesicles, could offer the best of both worlds is discussed. Through these topics, novel leads for further research are provided and, more importantly, gain insight in what the liposome field and the EV field can learn from each other.

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From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer

Cited by 31 publications

References 27 publications

A reduced Gompertz model for predicting tumor age using a population approach

A reduced Gompertz model for predicting tumor age using a population approach

Prototyping Trastuzumab Docetaxel Immunoliposomes with a New FCM-Based Method to Quantify Optimal Antibody Density on Nanoparticles

Liposomes and Extracellular Vesicles as Drug Delivery Systems: A Comparison of Composition, Pharmacokinetics, and Functionalization

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