Cytosolic Delivery of Membrane-Impermeable Molecules in Dendritic Cells Using pH-Responsive Core−Shell Nanoparticles

Hu, Yuhua; Litwin, Tamara R.; Nagaraja, Ankur K.; Kwong, Brandon; Katz, Joshua S.; Watson, Nicki; Irvine, Darrell J.

doi:10.1021/nl071542i

Cited by 289 publications

(300 citation statements)

References 57 publications

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“…To corroborate this pH-sensitive activity of the NPs at intracellular level, we used calcein as an endosomal tracer molecule, which is internalized by the cell through endocytosis and is used to monitor the stability of endosomes following NP uptake [35]. In the absence of NPs, endososomal compartmentalization of calcein was observed, which indicates that the endosome membranes were not damaged [35].…”

Section: Discussionmentioning

confidence: 99%

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In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles

et al. 2013

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Nanoparticles with pH-sensitive behavior may enhance the success of chemotherapy in many cancers by efficient intracellular drug delivery. Here, we investigated the effect of a bioactive surfactant with pH-sensitive properties on the antitumor activity and intracellular behavior of methotrexate-loaded chitosan nanoparticles (MTX-CS-NPs). NPs were prepared using a modified ionotropic complexation process, in which was included the surfactant derived from N α ,N ε -dioctanoyl lysine with an inorganic lithium counterion. The pH-sensitive behavior of NPs allowed accelerated release of MTX in an acidic medium, as well as membrane-lytic pH-dependent activity, which facilitated the cytosolic delivery of endocytosed materials. Moreover, our results clearly proved that MTX-CS-NPs were more active against the tumor HeLa and MCF-7 cell lines than the free drug. The feasibilty of using NPs to target acidic tumor extracellular pH was also shown, as cytotoxicity against cancer cells was greater in a mildly acidic environment. Finally, the combined physicochemical and pH-sensitive properties of NPs generally allowed the entrapped drug to induce greater cell cycle arrest and apoptotic effects. Therefore, our overall results suggest that pH-sensitive MTX-CS-NPs could be potentially useful as a carrier system for tumor and intracellular drug delivery in cancer therapy.

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Section: Discussionmentioning

confidence: 99%

“…Calcein, a membrane-impermeant fluorophore, was used as a model drug molecule and tracer to monitor the stability of endosomes following vesicle uptake [35]. HeLa cells were …”

Section: Cell Uptake Studies -Intracellular Release Of Calceinmentioning

confidence: 99%

In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles

et al. 2013

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“…The use of such polymers is, however, hampered by cytotoxicity associated with polyethylene imine's contact with the cell's membranes. To retain the proton-sponge effect yet eliminate cytotoxicity, core-shell nanoparticles have been studied using sequential emulsion polymerization, first of a secondary-aminecontaining monomer of appropriate pK a (diethylaminoethyl methacrylate), to form a core, and then of a second monomer, to form a corona (or shell) 59 . Regional separation of the functions of the particle led to favourable cytosolic release, through endosomal disruption by means of the proton-sponge effect, with markedly lower cytotoxicity than caused by free polyethylene imine 60 .…”

Section: Materials For Intracellular Targetingmentioning

confidence: 99%

Materials engineering for immunomodulation

Hubbell

Thomas

Swartz

2009

Nature

513

428

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The engineering of materials that can modulate the immune system is an emerging field that is developing alongside immunology. For therapeutic ends such as vaccine development, materials are now being engineered to deliver antigens through specific intracellular pathways, allowing better control of the way in which antigens are presented to one of the key types of immune cell, T cells. Materials are also being designed as adjuvants, to mimic specific 'danger' signals in order to manipulate the resultant cytokine environment, which influences how antigens are interpreted by T cells. In addition to offering the potential for medical advances, immunomodulatory materials can form well-defined model systems, helping to provide new insight into basic immunobiology.The term 'immunobioengineering' is used to describe efforts by immunologists and engineers to design materials, delivery vehicles and molecules both to manipulate and to better understand the immune system. Examples are the engineering of material surfaces to induce or prevent complement activation, the engineering of adjuvants to activate the immune system, the engineering of antigen or adjuvant carriers for subunit vaccine delivery, and the engineering of microenvironments to determine the interaction kinetics of mature dendritic cells and naive T cells. These advances not only will contribute to prophylactic vaccine strategies for infectious diseases but also are likely to affect immunotherapeutics, particularly for cancer, and new approaches to prevent or treat allergies and autoimmune diseases. The field is rapidly evolving along with advances in our understanding of immunology and is also contributing to our knowledge of basic immunology.In this Review, we describe the current state of immunobioengineering as it intersects with the field of materials science, and we give a perspective on its current and future directions. We focus on materials for immunomodulation, particularly with respect to dendritic-cell modulation. We begin by providing a brief introduction to the targets for delivery: the types of cell that materials are being designed to target, the tissues in which those cells reside, the intracellular compartments within those cells, and the influence that delivery to those particular compartments has on immunological outcome. We then discuss the biomolecular payloads used to activate immune cells and the design of the materials used to deliver those 'danger' signals along with, in the context of vaccination, antigens. Finally, we highlight materials approaches that are being developed to explore basic immunological function, especially how dendritic cells and T cells interact. Tissue and cellular targetsAs the general goals of immunobioengineering are to probe and manipulate the immune system, we start with a general discussion of tissue, cellular and subcellular targets -what we want to target and why -to guide the design principles discussed below.The immune cells most frequently targeted include B cells, macrophages and dendritic cells, wh...

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“…Therapeutics agents, including antitumor drugs, act at intracellular sites and, thus, their clinical efficacy depends on efficient intracellular trafficking (Hu et al 2007;Plank et al 1998). …”

Section: Ph-dependent Membrane-lytic Activity Of Nanoparticlesmentioning

confidence: 99%

Inclusion of a pH-responsive amino acid-based amphiphile in methotrexate-loaded chitosan nanoparticles as a delivery strategy in cancer therapy

et al. 2015

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The encapsulation of antitumor drugs in nanosized systems with pH-sensitive behavior is a promissing approach that may enhance the success of chemotherapy in many cancers. The nanocarrier dependence on pH might trigger an efficient delivery of the encapsulated drug both in the acidic extracellular environment of tumors and, especially, in the intracellular compartments through disruption of endosomal membrane. In this context, here we reported the preparation of chitosan-based nanoparticles encapsulating methotrexate as a model drug (MTX-CS-NPs), which comprises the incorporation of an amino acid-based amphiphile with pHresponsive properties (77KS) on the ionotropic complexation process. The presence of 77KS clearly gives a pH-sensitive behavior to NPs, which allowed accelerated release of MTX with decreasing pH as well as pH-dependent membrane-lytic activity. This latter performance demonstrates the potential of these NPs to facilitate cytosolic delivery of endocytosed materials.Outstandingly, the cytotoxicity of MTX-loaded CS-NPs was higher than free drug to MCF-7 tumor cells and, to a lesser extent, to HeLa cells. Based on the overall results, MTX-CS-NPs modified with the pH-senstive surfactant 77KS could be potentially useful as a carrier system for intracellular drug delivery and, thus, a promising targeting anticancer chemotherapeutic agent.

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Cytosolic Delivery of Membrane-Impermeable Molecules in Dendritic Cells Using pH-Responsive Core−Shell Nanoparticles

Cited by 289 publications

References 57 publications

In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles

In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles

Materials engineering for immunomodulation

Inclusion of a pH-responsive amino acid-based amphiphile in methotrexate-loaded chitosan nanoparticles as a delivery strategy in cancer therapy

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