A randomized controlled phase II trial of a novel composition of paclitaxel embedded into neutral and cationic lipids targeting tumor endothelial cells in advanced triple-negative breast cancer (TNBC)

Awada, Ahmad; Bondarenko, Igor; Bonneterre, J.; Nowara, Elżbieta; Ferrero, Jean-­Marc; Bakshi, Ashish; Wilke, Celine; Piccart, Martine

doi:10.1093/annonc/mdu025

Cited by 115 publications

(53 citation statements)

References 28 publications

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“…Thus, whereas previous studies (including clinical trials) of CL-based carriers have exclusively focused on 3 mol% PTXL content (i.e. near the CL solubility limit) [35,41,51], our study has revealed two distinctly new PTXL composition regimes, below and above 3 mol% PTXL content, where CL PTXL NPs exhibit improved efficacy. Furthermore, our results demonstrate that the time of NP delivery after liposome hydration is a critical parameter affecting efficacy.…”

Section: Introductionmentioning

confidence: 87%

Distinct solubility and cytotoxicity regimes of paclitaxel-loaded cationic liposomes at low and high drug content revealed by kinetic phase behavior and cancer cell viability studies

et al. 2017

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Lipid-based particles are used worldwide in clinical trials as carriers of hydrophobic paclitaxel (PTXL) for cancer chemotherapy, albeit with little improvement over the standard-of-care. Improving efficacy requires an understanding of intramembrane interactions between PTXL and lipids to enhance PTXL solubilization and suppress PTXL phase separation into crystals. We studied the solubility of PTXL in cationic liposomes (CLs) composed of positively charged 2,3-dioleyloxypropyltrimethylammonium chloride (DOTAP) and neutral 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) as a function of PTXL membrane content and its relation to efficacy. Time-dependent kinetic phase diagrams were generated from observations of PTXL crystal formation by differential-interference-contrast microscopy. Furthermore, a new synchrotron small-angle x-ray scattering in situ methodology applied to DOTAP/DOPC/PTXL membranes condensed with DNA enabled us to detect the incorporation and time-dependent depletion of PTXL from membranes by measurements of variations in the membrane interlayer and DNA interaxial spacings. Our results revealed three regimes with distinct time scales for PTXL membrane solubility: hours for > 3 mol% PTXL (low), days for ≈ 3 mol% PTXL (moderate), and ≥ 20 days for < 3 mol% PTXL (long-term). Cell viability experiments on human cancer cell lines using CLPTXL nanoparticles (NPs) in the distinct CLPTXL solubility regimes reveal an unexpected dependence of efficacy on PTXL content in NPs. Remarkably, formulations with lower PTXL content and thus higher stability show higher efficacy than those formulated at the membrane solubility limit of ≈ 3 mol% PTXL (which has been the focus of most previous physicochemical studies and clinical trials of PTXL-loaded CLs). Furthermore, an additional high-efficacy regime is seen on occasion for liposome compositions with PTXL ≥ 9 mol% applied to cells at short time scales (hours) after formation. At longer time scales (days), CLPTXL NPs with ≥ 3 mol% PTXL lose efficacy while formulations with 1–2 mol% PTXL maintain high efficacy. Our findings underscore the importance of understanding the relationship of the kinetic phase behavior and physicochemical properties of CLPTXL NPs to efficacy.

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Section: Introductionmentioning

confidence: 87%

Distinct solubility and cytotoxicity regimes of paclitaxel-loaded cationic liposomes at low and high drug content revealed by kinetic phase behavior and cancer cell viability studies

et al. 2017

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“…Human papilloma virus [107][108][109][110] It was reported that cationic liposomes could selectively accumulate in tumorous vascular endothelial cells so that cationic liposomes were made from antitumor carriers that would target tumorous vascular to reduce the toxicity of antitumor drugs. 111,112 CUR-loaded cationic liposomes were prepared by Saengkrit et al 113 using conventional thin-film hydration method and investigated the inhibitory activity against HPV18-and HPV16-positive cells. The results revealed that half maximal inhibitory concentration of Hela and SiHa cells was 21 μM and 16 μM, respectively.…”

Section: Cervical Cancermentioning

confidence: 99%

Liposomal curcumin and its application in cancer

Feng¹,

Wei²,

Lee³

et al. 2017

IJN

316

208

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Curcumin (CUR) is a yellow polyphenolic compound derived from the plant turmeric. It is widely used to treat many types of diseases, including cancers such as those of lung, cervices, prostate, breast, bone and liver. However, its effectiveness has been limited due to poor aqueous solubility, low bioavailability and rapid metabolism and systemic elimination. To solve these problems, researchers have tried to explore novel drug delivery systems such as liposomes, solid dispersion, microemulsion, micelles, nanogels and dendrimers. Among these, liposomes have been the most extensively studied. Liposomal CUR formulation has greater growth inhibitory and pro-apoptotic effects on cancer cells. This review mainly focuses on the preparation of liposomes containing CUR and its use in cancer therapy.

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“…The paclitaxel can then attack the newly formed tumor vessels and cut off blood supply to the tumor. In a trial of 141 TNBC patients, at 16 weeks the disease free survival was 59.1% in the Endo-Tag-1/paclitaxel combination group compared to 48% in the paclitaxel only group 90 .…”

Section: Current Advances In Cancer Nanotechnology For Tnbcmentioning

confidence: 99%

“…Endo-Tag-1 is a paclitaxel embedded liposomal nanoparticle that has been evaluated in a phase II clinical trial for advanced TNBC 90 . Its mechanism of action involves the negatively charged, newly formed tumor vasculature attracting the cationic liposome carrying the paclitaxel thus facilitating drug delivery.…”

Section: Current Advances In Cancer Nanotechnology For Tnbcmentioning

confidence: 99%

Targeted nanoparticles for image‐guided treatment of triple‐negative breast cancer: clinical significance and technological advances

Miller‐Kleinhenz

Bozeman

Yang

2015

WIREs Nanomed Nanobiotechnol

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Effective treatment of triple negative breast cancer (TNBC) with its aggressive tumor biology, highly heterogeneous tumor cells, and poor prognosis requires an integrated therapeutic approach that addresses critical issues in cancer therapy. Multifunctional nanoparticles with the abilities of targeted drug delivery and non-invasive imaging for monitoring drug delivery and responses to therapy, such as theranostic nanoparticles, hold great promise towards the development of novel therapeutic approaches for the treatment of TNBC using a single therapeutic platform. The biological and pathological characteristics of TNBC provide insight into several potential molecular targets for current and future nanoparticle based therapeutics. Extensive tumor stroma, highly proliferative cells, and a high rate of drug-resistance are all barriers that must be appropriately addressed in order for these nanotherapeutic platforms to be effective. Utilization of the enhanced permeability and retention (EPR) effect coupled with active targeting of cell surface receptors expressed by TNBC cells, and tumor associated endothelial cells, stromal fibroblasts and macrophages is likely to overcome such barriers to facilitate more effective drug delivery. An in depth summary of current studies investigating targeted nanoparticles in preclinical TNBC mouse and human xenograft models is presented. This review aims to outline the current status of nanotherapeutic options for TNBC patients, identification of promising molecular targets, challenges associated with the development of targeted nanotherapeutics, the research done by our group as well as others and future perspectives on the nanomedicine field and ways to translate current preclinical studies into the clinic.

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A randomized controlled phase II trial of a novel composition of paclitaxel embedded into neutral and cationic lipids targeting tumor endothelial cells in advanced triple-negative breast cancer (TNBC)

Cited by 115 publications

References 28 publications

Distinct solubility and cytotoxicity regimes of paclitaxel-loaded cationic liposomes at low and high drug content revealed by kinetic phase behavior and cancer cell viability studies

Distinct solubility and cytotoxicity regimes of paclitaxel-loaded cationic liposomes at low and high drug content revealed by kinetic phase behavior and cancer cell viability studies

Liposomal curcumin and its application in cancer

Targeted nanoparticles for image‐guided treatment of triple‐negative breast cancer: clinical significance and technological advances

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