Matrix metalloproteinase 2-responsive micelle for siRNA delivery.

Systemic delivery of small interfering RNA (siRNA) into cancer cells remains the major obstacle to siRNA drug development. An ideal siRNA delivery vehicle for systemic administration should have long circulation time in blood, accumulate at tumor site, and sufficiently internalize into cancer cells for high-efficiency of gene silence. Herein, we report a core-shell Micelleplex delivery system that made from block copolymer bearing poly(ethylene glycol) (PEG), matrix metalloproteinase 2 (MMP-2)-degradable peptide PLG*LAG, cationic cell penetrating peptide polyarginine r9 and poly(ε-caprolactone) (PCL) for siRNA delivery. We show clear evidences in vitro and in vivo to prove that the micelle carrying siRNA can circulate enough time in blood, enrich accumulation at tumor sites, shed the PEG layer when triggered by tumor overexpressing MMP-2, and then the exposing cell penetrating peptide r9 enhanced cellular uptake of siRNA. Accordingly, this design strategy enhances the inhibition of breast tumor growth following systemic injection of this system carrying siRNA against Polo-like kinase 1, which demonstrating this Micelleplex can be a potential delivery system for systemic siRNA delivery in cancer therapy.

[1]  H Akita,et al.  Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid , 2007, Gene Therapy.

[2]  Jun Wang,et al.  Anti-Her2 single-chain antibody mediated DNMTs-siRNA delivery for targeted breast cancer therapy. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[3]  Paula T Hammond,et al.  Layer-by-layer nanoparticles with a pH-sheddable layer for in vivo targeting of tumor hypoxia. , 2011, ACS nano.

[4]  G. Lu,et al.  Magnetic silica spheres with large nanopores for nucleic acid adsorption and cellular uptake. , 2012, Biomaterials.

[5]  S. Simões,et al.  Sterically Stabilized pH-sensitive Liposomes , 1997, The Journal of Biological Chemistry.

[6]  Qiang Zhang,et al.  Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA delivery. , 2012, Biomaterials.

[7]  Y. Barenholz,et al.  Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. , 1994, Cancer research.

[8]  Jason L. Townson,et al.  Delivery of small interfering RNA by peptide-targeted mesoporous silica nanoparticle-supported lipid bilayers. , 2012, ACS nano.

[9]  Jun Wang,et al.  Surface Charge Switchable Nanoparticles Based on Zwitterionic Polymer for Enhanced Drug Delivery to Tumor , 2012, Advanced materials.

[10]  Chen Jiang,et al.  Tumor targeting and microenvironment-responsive nanoparticles for gene delivery. , 2013, Biomaterials.

[11]  Jia Guo,et al.  Redox/pH dual stimuli-responsive biodegradable nanohydrogels with varying responses to dithiothreitol and glutathione for controlled drug release. , 2012, Biomaterials.

[12]  Jun Wang,et al.  N-acetylgalactosamine functionalized mixed micellar nanoparticles for targeted delivery of siRNA to liver. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[13]  R. Langer,et al.  Lipid‐based nanotherapeutics for siRNA delivery , 2010, Journal of internal medicine.

[14]  Mark E. Davis,et al.  PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. , 2004, European journal of cell biology.

[15]  D. Baltimore,et al.  Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Sheng,et al.  Star-branched amphiphilic PLA-b-PDMAEMA copolymers for co-delivery of miR-21 inhibitor and doxorubicin to treat glioma. , 2014, Biomaterials.

[17]  Young-Wook Won,et al.  Poly(oligo-D-arginine) with internal disulfide linkages as a cytoplasm-sensitive carrier for siRNA delivery. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[18]  H. Sato,et al.  Expression of genes encoding type IV collagen-degrading metalloproteinases and tissue inhibitors of metalloproteinases in various human tumor cells. , 1992, Oncogene.

[19]  M. Hope,et al.  Characterization of the inhibitory effect of PEG-lipid conjugates on the intracellular delivery of plasmid and antisense DNA mediated by cationic lipid liposomes. , 2002, Biochimica et biophysica acta.

[20]  Jun Wang,et al.  Polymeric‐Micelle‐Based Nanomedicine for siRNA Delivery , 2013 .

[21]  H. Gu,et al.  A mesoporous silica nanoparticle--PEI--fusogenic peptide system for siRNA delivery in cancer therapy. , 2013, Biomaterials.

[22]  N. Kim,et al.  RNA interference in vitro and in vivo using an arginine peptide/siRNA complex system. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[23]  L. Kotra,et al.  Potent and Selective Mechanism-Based Inhibition of Gelatinases , 2000 .

[24]  Jin-Zhi Du,et al.  Sheddable ternary nanoparticles for tumor acidity-targeted siRNA delivery. , 2012, ACS nano.

[25]  J. Burnett,et al.  RNA-based therapeutics: current progress and future prospects. , 2012, Chemistry & biology.

[26]  Yang Liu,et al.  In vivo delivery of RNAi with lipid-based nanoparticles. , 2011, Annual review of biomedical engineering.

[27]  Mark B. Carter,et al.  Cell-specific delivery of diverse cargos by bacteriophage MS2 virus-like particles. , 2011, ACS nano.

[28]  R K Jain,et al.  Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. , 1995, Cancer research.

[29]  Qiang Zhang,et al.  Core-shell type lipid/rPAA-Chol polymer hybrid nanoparticles for in vivo siRNA delivery. , 2014, Biomaterials.

[30]  Jun Wang,et al.  Targeted Delivery of PLK1-siRNA by ScFv Suppresses Her2+ Breast Cancer Growth and Metastasis , 2012, Science Translational Medicine.

[31]  Z. Werb,et al.  Matrix Metalloproteinases: Regulators of the Tumor Microenvironment , 2010, Cell.

[32]  K. G. Rajeev,et al.  Rational design of cationic lipids for siRNA delivery , 2010, Nature Biotechnology.

[33]  U. Schubert,et al.  Poly(ethylene glycol) in Drug Delivery: Pros and Cons as Well as Potential Alternatives. , 2011 .

[34]  Beverly L. Davidson,et al.  Current prospects for RNA interference-based therapies , 2011, Nature Reviews Genetics.

[35]  W. Saltzman,et al.  Octa-functional PLGA nanoparticles for targeted and efficient siRNA delivery to tumors. , 2012, Biomaterials.

[36]  H. Maeda,et al.  Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[37]  Lin Zhu,et al.  Matrix metalloprotease 2-responsive multifunctional liposomal nanocarrier for enhanced tumor targeting. , 2012, ACS nano.

[38]  S. Wise.  Nanocarriers as an emerging platform for cancer therapy , 2007 .

[39]  Jin-Zhi Du,et al.  A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy. , 2011, Biomaterials.

[40]  V. Awasthi,et al.  Circulation and biodistribution profiles of long-circulating PEG-liposomes of various sizes in rabbits. , 2003, International journal of pharmaceutics.

[41]  Christopher E. Nelson,et al.  Matrix Metalloproteinase Responsive, Proximity‐Activated Polymeric Nanoparticles for siRNA Delivery , 2013, Advanced functional materials.

[42]  Roger Y Tsien,et al.  Tumor imaging by means of proteolytic activation of cell-penetrating peptides. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Noritada Kaji,et al.  Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid. , 2011, Biomaterials.

[44]  S. W. Kim,et al.  Arginine-grafted bioreducible poly(disulfide amine) for gene delivery systems. , 2009, Biomaterials.

[45]  Matthias John,et al.  RNAi-mediated gene silencing in non-human primates , 2006, Nature.

[46]  A. Judge,et al.  Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice. , 2009, The Journal of clinical investigation.

[47]  Jin-Zhi Du,et al.  Tailor-made dual pH-sensitive polymer-doxorubicin nanoparticles for efficient anticancer drug delivery. , 2011, Journal of the American Chemical Society.