Microtubule targeted therapeutics loaded polymeric assembled nanospheres for potentiation of antineoplastic activity.

Polymeric nanoassemblies represent an attractive strategy for efficient cellular internalization of microtubule targeted anticancer drugs. Using dynamic light scattering, zeta potential, transmission electron microscopy and scanning electron microscopy, the physical properties and surface morphology of microtubule-binding PEGylated PLGA assembled nanospheres (100-200 nm) were analyzed. The present approach leads to strong internalization as observed by confocal laser scanning microscopy and transmission electron microscopy in hepatocarcinoma cells. The effect of these nanoassemblies on microtubules and mitosis were explored using immunofluorescence microscopy. The effects of these nanoassemblies on cancer cell proliferation and cell death revealed their antitumor enhancing effects. Perturbation of the microtubule assembly, mitosis and nuclear modulations potentiated the antineoplastic effects delivered via nanospheres in hepatocarcinoma cells. The extensive biomolecular and physical characterizations of the synthesized nanoassemblies will help to design potent therapeutic materials and the present approach can be applied to deliver microtubule-targeted drugs for liver cancer therapy.

[1]  P. Kaldis,et al.  The Complex Relationship between Liver Cancer and the Cell Cycle: A Story of Multiple Regulations , 2014, Cancers.

[2]  A. Surolia,et al.  CXI-benzo-84 reversibly binds to tubulin at colchicine site and induces apoptosis in cancer cells. , 2013, Biochemical pharmacology.

[3]  Praveen K. Gajula,et al.  A synthetic dolastatin 10 analogue suppresses microtubule dynamics, inhibits cell proliferation, and induces apoptotic cell death. , 2013, Journal of medicinal chemistry.

[4]  Guopeng Shen,et al.  Tissue distribution of 2-methoxyestradiol nanosuspension in rats and its antitumor activity in C57BL/6 mice bearing lewis lung carcinoma , 2012, Drug delivery.

[5]  N. Zhang,et al.  Micelle-like nanoassemblies based on polymer–drug conjugates as an emerging platform for drug delivery , 2012, Expert opinion on drug delivery.

[6]  Ling Ye,et al.  Preparation and cytotoxicity of poly (DL-lactide-co-glycolide) microspheres encapsulating 2-methoxyestradiol , 2012, Drug delivery.

[7]  Omid C Farokhzad,et al.  Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. , 2012, Chemical Society reviews.

[8]  M. Harrison,et al.  A phase II study of 2-methoxyestradiol (2ME2) NanoCrystal® dispersion (NCD) in patients with taxane-refractory, metastatic castrate-resistant prostate cancer (CRPC) , 2011, Investigational New Drugs.

[9]  Richard A. Stanton,et al.  Drugs that target dynamic microtubules: A new molecular perspective , 2011, Medicinal research reviews.

[10]  D. Mukhopadhyay,et al.  Structure-activity study to develop cationic lipid-conjugated haloperidol derivatives as a new class of anticancer therapeutics. , 2011, Journal of medicinal chemistry.

[11]  S. Verenich,et al.  Therapeutic promises of 2-methoxyestradiol and its drug disposition challenges. , 2010, Molecular pharmaceutics.

[12]  Y. Bae,et al.  Polymer nanoassemblies for cancer treatment and imaging. , 2010, Therapeutic delivery.

[13]  Hong Ding,et al.  Development of PEGylated PLGA nanoparticle for controlled and sustained drug delivery in cystic fibrosis , 2010, Journal of nanobiotechnology.

[14]  L. Dai,et al.  Preparation of cells for assessing ultrastructural localization of nanoparticles with transmission electron microscopy , 2010, Nature Protocols.

[15]  Atul Gupta,et al.  Design, synthesis and biological evaluation of estradiol-chlorambucil hybrids as anticancer agents. , 2010, Bioorganic & medicinal chemistry letters.

[16]  P. Fong,et al.  PEGylated PLGA nanoparticles for the improved delivery of doxorubicin. , 2009, Nanomedicine : nanotechnology, biology, and medicine.

[17]  E. Matera,et al.  Beta3-tubulin is induced by estradiol in human breast carcinoma cells through an estrogen-receptor dependent pathway. , 2009, Cell motility and the cytoskeleton.

[18]  J. Bruix,et al.  Molecular targeted therapies in hepatocellular carcinoma , 2008, Hepatology.

[19]  D. Panda,et al.  Kinetic stabilization of microtubule dynamics by estramustine is associated with tubulin acetylation, spindle abnormalities, and mitotic arrest. , 2008, Cancer research.

[20]  M. R. Kumar,et al.  PLGA nanoparticles for oral delivery of hydrophobic drugs: influence of organic solvent on nanoparticle formation and release behavior in vitro and in vivo using estradiol as a model drug. , 2008, Journal of pharmaceutical sciences.

[21]  Robert Langer,et al.  Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers , 2008, Proceedings of the National Academy of Sciences.

[22]  V. Bhardwaj,et al.  Estradiol loaded PLGA nanoparticles for oral administration: effect of polymer molecular weight and copolymer composition on release behavior in vitro and in vivo. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[23]  Robert Langer,et al.  Formulation of functionalized PLGA-PEG nanoparticles for in vivo targeted drug delivery. , 2007, Biomaterials.

[24]  Catrin Albrecht,et al.  Cellular responses to nanoparticles: Target structures and mechanisms , 2007 .

[25]  Kanyawim Kirtikara,et al.  Sulforhodamine B colorimetric assay for cytotoxicity screening , 2006, Nature Protocols.

[26]  Arezou A Ghazani,et al.  Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. , 2006, Nano letters.

[27]  S. Fesik Promoting apoptosis as a strategy for cancer drug discovery , 2005, Nature Reviews Cancer.

[28]  M. Ferrari Cancer nanotechnology: opportunities and challenges , 2005, Nature Reviews Cancer.

[29]  M. Jordan,et al.  Microtubules as a target for anticancer drugs , 2004, Nature Reviews Cancer.

[30]  V. D. Ramirez,et al.  Estradiol and Testosterone Have Opposite Effects on Microtubule Polymerization , 2003, Neuroendocrinology.

[31]  Jayanth Panyam,et al.  Biodegradable nanoparticles for drug and gene delivery to cells and tissue. , 2003, Advanced drug delivery reviews.

[32]  T. Lavallee,et al.  2-Methoxyestradiol Inhibits Proliferation and Induces Apoptosis Independently of Estrogen Receptors α and β , 2002 .

[33]  S. Lowe,et al.  Apoptosis in cancer. , 2000, Carcinogenesis.

[34]  Y. Sato,et al.  Microtubule disruption induced by estradiol in estrogen receptor-positive and -negative human breast cancer cell lines. , 1994, Carcinogenesis.

[35]  V. Torchilin,et al.  Biodegradable long-circulating polymeric nanospheres. , 1994, Science.

[36]  D. Scudiero,et al.  New colorimetric cytotoxicity assay for anticancer-drug screening. , 1990, Journal of the National Cancer Institute.

[37]  A. Jemal,et al.  Cancer statistics, 2014 , 2014, CA: a cancer journal for clinicians.

[38]  A. Gomes,et al.  Liposome and protein based stealth nanoparticles. , 2013, Faraday discussions.

[39]  Myung Chul Choi,et al.  Ion specific effects in bundling and depolymerization of taxol-stabilized microtubules. , 2013, Faraday discussions.