Cytosolic Delivery of Liposomally Targeted Proteins Induced by Photochemical Internalization

Fretz, Marjan M.; Høgset, Anders; Koning, Gerben A.; Jiskoot, Wim; Storm, Gert

doi:10.1007/s11095-007-9338-9

Cited by 38 publications

(46 citation statements)

References 28 publications

(28 reference statements)

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“…Translocation of GzmB across a PFN-induced arc may resemble the action of cell-penetrating peptides (CPP). The latter penetrate into cells directly across the plasma membrane 33,34 as well as induce endocytic uptake. Remarkably, penetration of CPPs is augmented by externalized PS, an effect further increased by depleting membrane cholesterol.…”

Section: Discussionmentioning

confidence: 99%

Perforin oligomers form arcs in cellular membranes: a locus for intracellular delivery of granzymes

et al. 2014

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Perforin-mediated cytotoxicity is an essential host defense, in which defects contribute to tumor development and pathogenic disorders including autoimmunity and autoinflammation. How perforin (PFN) facilitates intracellular delivery of pro-apoptotic and inflammatory granzymes across the bilayer of targets remains unresolved. Here we show that cellular susceptibility to granzyme B (GzmB) correlates with rapid PFN-induced phosphatidylserine externalization, suggesting that pores are formed at a protein-lipid interface by incomplete membrane oligomers (or arcs). Supporting a role for these oligomers in protease delivery, an anti-PFN antibody (pf-80) suppresses necrosis but increases phosphatidylserine flip-flop and GzmB-induced apoptosis. As shown by atomic force microscopy on planar bilayers and deep-etch electron microscopy on mammalian cells, pf-80 increases the proportion of arcs which correlates with the presence of smaller electrical conductances, while large cylindrical pores decline. PFN appears to form arc structures on target membranes that serve as minimally disrupting conduits for GzmB translocation. The role of these arcs in PFN-mediated pathology warrants evaluation where they may serve as novel therapeutic targets. Cell Death and Differentiation ( The cytotoxic cell granule-secretory pathway depends on perforin (PFN) to deliver granzyme (Gzm) proteases to the cytosol of target cells where they induce apoptosis and other biological effects, such as inflammation. 1 Ring-shaped transmembrane PFN pores hereafter called 'cylindrical pores', are presumed to act as the gateway for cytosolic entry, either at the plasma membrane or after endocytosis. [2][3][4] In either case the highly cationic Gzms are thought to diffuse through these cylindrical pores formed by poly-PFN. Nevertheless, a mechanistic understanding of the phenomenon (how the cationic globular protein exchanges from its carrier proteoglycan, serglycin, to the pore and crosses the plasma and/or vesicular membranes) has been lacking due to limitations in imaging technology and in our detailed understanding of the molecular forms that PFN may adopt following interaction with a target cell plasma membrane.Here we show under conditions where cylindrical pore formation is minimal, 5 that granzyme B (GzmB) translocation readily occurs. We previously demonstrated that a prelude to granzyme translocation is PFN-mediated, Ca-independent phosphatidylserine (PS) externalization (flip-flop) measured by annexin-V and lactadherin binding. 6 This rapid PS flip-flop also occurs when mouse CD8 cells contact antigen-pulsed target cells. Inasmuch as the proteinaceous cylinders offer a formidable barrier to lipid flow, we have speculated that the observed movement of anionic phospholipids to the external leaflet is due to the formation of proteo-lipidic structures, which consists of oligomerized PFN monomers bearing an arc morphology and plasma membrane lipids. [6][7][8] In the work reported here, the topology of PFN embedded into homogeneous planar bilayers and t...

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Section: Discussionmentioning

confidence: 99%

Perforin oligomers form arcs in cellular membranes: a locus for intracellular delivery of granzymes

et al. 2014

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“…Therapeutics and targeting systems that enter the cell through the endosomal pathway are most often subjected to lysosomal degradation. To address these issues the technique of photochemical internalization (PCI) has been incorporated with nanoparticle carriers [84]. This technique employs amphiphilic photosensitizers that exhibit preferential membrane localization [84].…”

Section: Drug and Photodynamic Therapiesmentioning

confidence: 99%

“…To address these issues the technique of photochemical internalization (PCI) has been incorporated with nanoparticle carriers [84]. This technique employs amphiphilic photosensitizers that exhibit preferential membrane localization [84]. Endocytosis of the photosensitizers leads to their incorporation in endosomal membranes [84].…”

Section: Drug and Photodynamic Therapiesmentioning

confidence: 99%

Multi-functional nanocarriers to overcome tumor drug resistance

Jabr-Milane¹,

Vlerken²,

Yadav³

et al. 2008

Cancer Treatment Reviews

376

251

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The development of resistance to variety of chemotherapeutic agents is one of the major challenges in effective cancer treatment. Tumor cells are able to generate a multi-drug resistance (MDR) phenotype due to microenvironmental selection pressures. This review addresses the use of nanotechnology-based delivery systems to overcome MDR in solid tumors. Our own work along with evidence from the literature illustrates the development of various types of engineered nanocarriers specifically designed to enhance tumor-targeted delivery through passive and active targeting strategies. Additionally, multi-functional nanocarriers are developed to enhance drug delivery and overcome MDR by either simultaneous or sequential delivery of resistance modulators (e.g., with P-glycoprotein substrates), agents that regulate intracellular pH, agents that lower the apoptotic threshold (e.g., with ceramide), or in combination with energy delivery (e.g., sound, heat, and light) to enhance the effectiveness of anticancer agents in refractory tumors. In preclinical studies, the use of multi-functional nanocarriers has shown significant promise in enhancing cancer therapy, especially against MDR tumors.

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“…PCI has been used successfully for the delivery of liposomes into the cytosol of targeted cells. Fretz et al loaded the protein toxin saporin into liposomes and incubated human ovarian carcinoma cells with these saporin loaded liposomes and the photosensitizer TPPS2a before applying varying light pulses [116]. The enhancement of cytotoxicity was dependent on the saporin concentration and illumination time with the highest efficacy at 120 s, the longest duration tested.…”

Section: Physicochemical Techniquesmentioning

confidence: 99%

Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins

Fuchs

Bachran²,

Flavell

et al. 2013

Antibodies

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Membranes are vital barriers by which cells control the flux of molecules and energy between their exterior and interior and also between their various intracellular compartments. While numerous transport systems exist for ions and small molecules, the cytosolic uptake of larger biological molecules and in particular antibody-targeted drugs, is a big challenge. Inducing leakage of the plasma membrane is unfavorable since the target cell specificity mediated by the antibody would likely be lost in this case. After binding and internalization, the antibody drug conjugates reach the endosomes. Thus, enforcing the endosomal escape of anti-tumor toxins without affecting the integrity of other cellular membranes is of paramount importance. Different strategies have been developed in the last decades to overcome endosomal accumulation and subsequent lysosomal degradation of targeted protein-based drugs. In this review we summarize the various efforts made to establish efficient techniques to disrupt the endosomal membrane barrier including the use of molecular ferries such as cell penetrating peptides or viral membrane fusion proteins, endosomal leakage inducing molecules such as saponins or monensin and physicochemical methods as represented by photochemical internalization.

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Cytosolic Delivery of Liposomally Targeted Proteins Induced by Photochemical Internalization

Cited by 38 publications

References 28 publications

Perforin oligomers form arcs in cellular membranes: a locus for intracellular delivery of granzymes

Perforin oligomers form arcs in cellular membranes: a locus for intracellular delivery of granzymes

Multi-functional nanocarriers to overcome tumor drug resistance

Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins

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