Immuno-LipoTRAIL: Targeted Delivery of TRAIL-Functionalized Liposomal Nanoparticles

Seifert, Oliver; Pollak, Nadine; Nusser, Anja; Steiniger, Frank; Rüger, Ronny; Pfizenmaier, Klaus; Kontermann, Roland E.

doi:10.1021/bc400517j

Cited by 37 publications

(43 citation statements)

References 30 publications

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“…It should also be noted that TRAIL liposomes tethered to the surface of circulating leukocytes exhibited a circulation half-life (Fig. 1) significantly longer than any previously described nanoparticle formulations of TRAIL [31-33]. Nanomedicine-based therapeutic approaches such as the one demonstrated here may hold the key to exploiting the potency of TRAIL within the circulation.…”

Section: Discussionmentioning

confidence: 66%

TRAIL-coated leukocytes that prevent the bloodborne metastasis of prostate cancer

Wayne

Chandrasekaran

Mitchell

et al. 2016

Journal of Controlled Release

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Prostate cancer, once it has progressed from its local to metastatic form, is a disease with poor prognosis and limited treatment options. Here we demonstrate an approach using nanoscale liposomes conjugated with E-selectin adhesion protein and Apo2L/TRAIL (TNF-related apoptosis-inducing ligand) apoptosis ligand that attach to the surface of leukocytes and rapidly clear viable cancer cells from circulating blood, both in human blood samples and in the living mouse. For the first time, it is shown that such an approach can be used to prevent the spontaneous formation and growth of metastatic tumors in an orthotopic xenograft model of prostate cancer, by greatly reducing the number of circulating tumor cells. We conclude that the use of circulating leukocytes as a carrier for the anti-cancer protein TRAIL could be an effective tool to directly target circulating tumor cells for the prevention of prostate cancer metastasis, and potentially other cancers that spread through the bloodstream.

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Section: Discussionmentioning

confidence: 66%

TRAIL-coated leukocytes that prevent the bloodborne metastasis of prostate cancer

Wayne

Chandrasekaran

Mitchell

et al. 2016

Journal of Controlled Release

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“…Furthermore, their elevated plasticity in terms of molecular manipulation makes exosomes more appealing than for instance liposomes, also tested for TRAIL delivery (12)(13)(14). Notably, covalently bound TRAIL carried by liposomes increased its therapeutic potential with respect to the recombinant soluble counterpart, sustaining our system of exosomes released by their donor cells with "natural" membrane TRAIL (48).…”

Section: Discussionmentioning

confidence: 99%

“…þ cells have been recently tested in preclinical setting to deliver TRAIL, with the aim of optimizing bioavailability and stability of this molecule (10)(11)(12)(13)(14)(15). An innovate option to deliver TRAIL could be to embed it within vesicular structures directly generated by TRAIL-expressing cells.…”

Section: Introductionmentioning

confidence: 99%

TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

Rivoltini

Chiodoni

Squarcina

et al. 2016

Clinical Cancer Research

160

120

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Purpose: Exosomes deliver signals to target cells and could thus be exploited as an innovative therapeutic tool. We investigated the ability of membrane TRAIL-armed exosomes to deliver proapoptotic signals to cancer cells and mediate growth inhibition in different tumor models.Experimental Methods and Results: K562 cells, transduced with lentiviral human membrane TRAIL, were used for the production of TRAIL þ exosomes, which were studied by nanoparticle tracking analysis, cytofluorimetry, immunoelectronmicroscopy, Western blot, and ELISA. In vitro, TRAIL þ exosomes induced more pronounced apoptosis (detected by Annexin V/ propidium iodide and activated caspase-3) in TRAIL-death receptor (DR)5 þ cells (SUDHL4 lymphoma and INT12 melanoma), with respect to the DR5 À DR4 þ KMS11 multiple myeloma. Intratumor injection of TRAIL þ exosomes, but not mock exosomes, induced growth inhibition of SUDHL4 (68%) and INT12 (51%), and necrosis in KMS11 tumors. After rapid blood clearance, systemically administered TRAIL þ exosomes accumulated in the liver, lungs, and spleen and homed to the tumor site, leading to a significant reduction of tumor growth (58%) in SUDHL4-bearing mice. The treatment of INT12-bearing animals promoted tumor necrosis and a not statistically significant tumor volume reduction. In KMS11-bearing mice, despite massive perivascular necrosis, no significant tumor growth inhibition was detected.Conclusions: TRAIL-armed exosomes can induce apoptosis in cancer cells and control tumor progression in vivo. Therapeutic efficacy was particularly evident in intratumor setting, while depended on tumor model upon systemic administration. Thanks to their ability to deliver multiple signals, exosomes thus represent a promising therapeutic tool in cancer.

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“…The actual molecular weight of scFv was around 27 kDa; however, after coupling we observed the expected shift to 30 kDa due to attachment of the 3 kDa PEG molecule. 31,49 Size change of the scFv after coupling was confirmed by dynamic light scattering, which showed an acceptable increase in the liposome size (around 10 nm) and PDI ( Table 1). Quantification of total lipid and protein levels of immunoliposomes resulted in a calculated assessment of the number of scFv (G8 and Hyb3) molecules to be between 13 and 23 per liposomes.…”

mentioning

confidence: 90%

Targeting melanoma with immunoliposomes coupled to anti-MAGE A1 TCR-like single-chain antibody

Saeed

Brakel

Zalba

et al. 2016

IJN

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Therapy of melanoma using T-cells with genetically introduced T-cell receptors (TCRs) directed against a tumor-selective cancer testis antigen (CTA) NY-ESO1 demonstrated clear antitumor responses in patients without side effects. Here, we exploited the concept of TCR-mediated targeting through introduction of single-chain variable fragment (scFv) antibodies that mimic TCRs in binding major histocompatibility complex-restricted CTA. We produced scFv antibodies directed against Melanoma AntiGEn A1 (MAGE A1) presented by human leukocyte antigen A1 (HLA-A1), in short M1/A1, and coupled these TCR-like antibodies to liposomes to achieve specific melanoma targeting. Two anti-M1/A1 antibodies with different ligand-binding affinities were derived from a phage-display library and reformatted into scFvs with an added cysteine at their carboxyl termini. Protein production conditions, ie, bacterial strain, temperature, time, and compartments, were optimized, and following production, scFv proteins were purified by immobilized metal ion affinity chromatography. Batches of pure scFvs were validated for specific binding to M1/A1-positive B-cells by flow cytometry. Coupling of scFvs to liposomes was conducted by employing different conditions, and an optimized procedure was achieved. In vitro experiments with immunoliposomes demonstrated binding of M1/A1-positive B-cells as well as M1/A1-positive melanoma cells and internalization by these cells using flow cytometry and confocal microscopy. Notably, the scFv with nonenhanced affinity of M1/A1, but not the one with enhanced affinity, was exclusively bound to and internalized by melanoma tumor cells expressing M1/A1. Taken together, antigen-mediated targeting of tumor cells as well as promoting internalization of nanoparticles by these tumor cells is mediated by TCR-like scFv and can contribute to melanoma-specific targeting.

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Immuno-LipoTRAIL: Targeted Delivery of TRAIL-Functionalized Liposomal Nanoparticles

Cited by 37 publications

References 30 publications

TRAIL-coated leukocytes that prevent the bloodborne metastasis of prostate cancer

TRAIL-coated leukocytes that prevent the bloodborne metastasis of prostate cancer

TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

Targeting melanoma with immunoliposomes coupled to anti-MAGE A1 TCR-like single-chain antibody

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