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Influence of surface chemistry on cytotoxicity and cellular uptake of nanocapsules in breast cancer and phagocytic cells.

ABSTRACT: The present work tests the hypothesis that stabilizers have a critical role on nanocarrier stealthiness and anticancer drug efficacy. Two different types of docetaxel (Doc)-loaded nanocapsules (NCs) stabilized with polysorbate 80 (NC(T80)) and polyvinyl alcohol (NC(PVA)) were synthesized using the emulsion solvent diffusion method. These NCs were characterized for particle mean diameter (PMD), drug content, morphology, surface composition, and degree of crystallinity. Furthermore, the cytotoxicity and cellular uptake of the NCs were investigated in MDA-MB 231 cells, THP-1 monocytes, and THP-1-derived macrophages. The optimized spherical NC(T80) had 123.02?±?14.6 nm, 0.27?±?0.1, and 101?±?37.0% for PMD, polydispersity index, and drug encapsulation efficiency, respectively. Doc release kinetics from NC(T80) and NC(PVA) mostly provided better fit to zero-order and Higuchi models, respectively. Powder X-ray diffraction (PXRD) and X-ray photoelectron spectroscopy (XPS) results revealed the presence of amorphous stabilizers on the surface of the NCs. At high drug concentration, the cytotoxicity of NC(T80) was substantially improved (1.3-1.6-fold) compared with that of NC(PVA) in MDA-MB 231 cells. The uptake of both NCs was inhibited by latrunculin A and dynasore, indicating an actin- and dynamin-dependent endocytosis in MDA-MB 231 cells. This occurred via a multifaceted mechanism involving clathrin, caveolin, cytoskeleton, and macropinocytosis. Interestingly, the uptake of NC(PVA) was 2.7-fold greater than that of NC(T80) and occurred through phagocytosis in monocytes and macrophages. This study demonstrates the potential impact of the surface chemistry on the cytotoxicity and phagocytic clearance of nanocarriers for a subsequent improvement of the efficacy of Doc intended for breast cancer chemotherapy.

SUBMITTER: Youm I

PROVIDER: S-EPMC4012057 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Influence of surface chemistry on cytotoxicity and cellular uptake of nanocapsules in breast cancer and phagocytic cells.

Youm Ibrahima I Bazzil Joseph D JD Otto Joseph W JW Caruso Anthony N AN Murowchick James B JB Youan Bi-Botti C BB

The AAPS journal 20140404 3

The present work tests the hypothesis that stabilizers have a critical role on nanocarrier stealthiness and anticancer drug efficacy. Two different types of docetaxel (Doc)-loaded nanocapsules (NCs) stabilized with polysorbate 80 (NC(T80)) and polyvinyl alcohol (NC(PVA)) were synthesized using the emulsion solvent diffusion method. These NCs were characterized for particle mean diameter (PMD), drug content, morphology, surface composition, and degree of crystallinity. Furthermore, the cytotoxici ...[more]

PMID: 24700270

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Project description:BackgroundPolymer nanoparticles (PNP) are becoming increasingly important in nanomedicine and food-based applications. Size and surface characteristics are often considered to be important factors in the cellular interactions of these PNP, although systematic investigations on the role of surface properties on cellular interactions and toxicity of PNP are scarce.ResultsFluorescent, monodisperse tri-block copolymer nanoparticles with different sizes (45 and 90 nm) and surface charges (positive and negative) were synthesized, characterized and studied for uptake and cytotoxicity in NR8383 and Caco-2 cells. All types of PNP were taken up by the cells. The positive smaller PNP45 (45 nm) showed a higher cytotoxicity compared to the positive bigger PNP(90) (90 nm) particles including reduction in mitochondrial membrane potential (??(m)), induction of reactive oxygen species (ROS) production, ATP depletion and TNF-? release. The negative PNP did not show any cytotoxic effect. Reduction in mitochondrial membrane potential (??(m)), uncoupling of the electron transfer chain in mitochondria and the resulting ATP depletion, induction of ROS and oxidative stress may all play a role in the possible mode of action for the cytotoxicity of these PNP. The role of receptor-mediated endocytosis in the intracellular uptake of different PNP was studied by confocal laser scanning microscopy (CLSM). Involvement of size and charge in the cellular uptake of PNP by clathrin (for positive PNP), caveolin (for negative PNP) and mannose receptors (for hydroxylated PNP) were found with smaller PNP45 showing stronger interactions with the receptors than bigger PNP(90).ConclusionsThe size and surface characteristics of polymer nanoparticles (PNP; 45 and 90 nm with different surface charges) play a crucial role in cellular uptake. Specific interactions with cell membrane-bound receptors (clathrin, caveolin and mannose) leading to cellular internalization were observed to depend on size and surface properties of the different PNP. These properties of the nanoparticles also dominate their cytotoxicity, which was analyzed for many factors. The effective reduction in the mitochondrial membrane potential (??(m)), uncoupling of the electron transfer chain in mitochondria and resulting ATP depletion, induction of ROS and oxidative stress likely all play a role in the mechanisms behind the cytotoxicity of these PNP.

Project description:Background and purposeA clinical need exists for targeted, safe, and effective sulfide donors. We recently reported that ammonium tetrathiomolybdate (ATTM) belongs to a new class of sulfide-releasing drugs. Here, we investigated the cellular uptake mechanisms of this drug class compared to sodium hydrosulfide (NaHS) and the effects of a thiometallate tungsten congener of ATTM, ammonium tetrathiotungstate (ATTT).Experimental approachIn vitro H2 S release was determined by headspace gas sampling of vials containing dissolved thiometallates. Thiometallate and NaHS bioactivity was assessed by spectrophotometry-derived sulfhaemoglobin formation. Cellular uptake dependence on the anion exchange protein (AE)-1 was investigated in human red blood cells. ATTM/glutathione interactions were assessed by LC-MS/MS. Rodent pharmacokinetic and pharmacodynamic studies focused on haemodynamics and inhibition of aerobic respiration.Key resultsATTM and ATTT both exhibit temperature-, pH-, and thiol-dependence of sulfide release. ATTM/glutathione interactions revealed the generation of inorganic and organic persulfides and polysulfides. ATTM showed greater ex vivo and in vivo bioactivity over ATTT, notwithstanding similar pharmacokinetic profiles. Cellular uptake mechanisms of the two drug classes are distinct; thiometallates show dependence on AE-1, while hydrosulfide itself was unaffected by inhibition of this pathway.Conclusions and implicationsThe cellular uptake of thiometallates relies upon a plasma membrane ion channel. This advances our pharmacological knowledge of this drug class, and further supports their utility as cell-targeted sulfide donor therapies. Our results indicate that, as a more stable form, ATTT is better suited as a copper chelator. ATTM, a superior sulfide donor, may additionally participate in intracellular redox recycling.Linked articlesThis article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.

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Influence of surface chemistry on cytotoxicity and cellular uptake of nanocapsules in breast cancer and phagocytic cells.

Publications

Influence of surface chemistry on cytotoxicity and cellular uptake of nanocapsules in breast cancer and phagocytic cells.

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