In Vivo Distribution of Polymeric Nanoparticles at the Whole-Body, Tumor, and Cellular Levels

PurposeBlock copolymer micelles (BCMs) were functionalized with indium-111 and/or epidermal growth factor (EGF), which enabled investigation of the in vivo transport of passively and actively targeted BCMs. The integration of conventional and image-based techniques afforded novel quantitative means to achieve an in-depth insight into the fate of polymeric nanoparticles in vivo.MethodsPharmacokinetics and biodistribution studies were performed in athymic mice bearing human breast xenografts to evaluate the whole-body transport of NT-BCMs (non-targeted, EGF-) and T-BCMs (targeted, EGF+). The intratumoral distribution of BCMs was investigated using MicroSPECT/CT and autoradiographic imaging, complemented with quantitative MATLAB® analyses. Tumors were fractionated for quantifying intracellular uptake of BCMs via γ-counting.ResultsThe intratumoral distribution of NT-BCMs and T-BCMs were found to be heterogeneous, and positively correlated with tumor vascularization (r > 0.68 ± 0.04). The enhanced in vivo cell uptake and cell membrane binding of T-BCMs were found to delay their clearance from tumors overexpressing EGFR, and therefore resulted in enhanced tumor accumulation for the T-BCMs in comparison to the NT-BCMs.ConclusionsAdequate passive targeting is required in order to achieve effective active targeting. Tumor physiology has a significant impact on the transvascular and intratumoral transport of passively and actively targeted BCMs.

[1]  Christine Allen,et al.  In vivo fate of unimers and micelles of a poly(ethylene glycol)-block-poly(caprolactone) copolymer in mice following intravenous administration. , 2007, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[2]  Kaushal Rege,et al.  Cancer-cell-phenotype-dependent differential intracellular trafficking of unconjugated quantum dots. , 2009, Small.

[3]  R. Reilly,et al.  Site-specific conjugation of HIV-1 tat peptides to IgG: a potential route to construct radioimmunoconjugates for targeting intracellular and nuclear epitopes in cancer , 2006, European Journal of Nuclear Medicine and Molecular Imaging.

[4]  Pauline Chu,et al.  A novel antiangiogenesis therapy using an integrin antagonist or anti-Flk-1 antibody coated 90Y-labeled nanoparticles. , 2004, International journal of radiation oncology, biology, physics.

[5]  F. Marcucci,et al.  Active targeting with particulate drug carriers in tumor therapy: fundamentals and recent progress. , 2004, Drug discovery today.

[6]  E. Fishman,et al.  Tumor transport physiology: implications for imaging and imaging-guided therapy. , 2001, AJR. American journal of roentgenology.

[7]  G. Raposo,et al.  Exosomes: endosomal-derived vesicles shipping extracellular messages. , 2004, Current opinion in cell biology.

[8]  C. Allen,et al.  Epidermal growth factor-conjugated poly(ethylene glycol)-block- poly(delta-valerolactone) copolymer micelles for targeted delivery of chemotherapeutics. , 2006, Bioconjugate chemistry.

[9]  Yaping Li,et al.  Targeted nanoassembly loaded with docetaxel improves intracellular drug delivery and efficacy in murine breast cancer model. , 2008, Molecular pharmaceutics.

[10]  K. Mann,et al.  Improved drug delivery to cancer cells: a method using magnetoliposomes that target epidermal growth factor receptors. , 2005, Medical hypotheses.

[11]  K. P. Murphy,et al.  Entropy in biological binding processes: Estimation of translational entropy loss , 1994, Proteins.

[12]  C. Allen,et al.  Block copolymer micelles for delivery of cancer therapy: transport at the whole body, tissue and cellular levels. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[13]  J. Hwang,et al.  N-acetyl histidine-conjugated glycol chitosan self-assembled nanoparticles for intracytoplasmic delivery of drugs: endocytosis, exocytosis and drug release. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[14]  G. Parmiani,et al.  Tumour-released exosomes and their implications in cancer immunity , 2008, Cell Death and Differentiation.

[15]  S M Moghimi,et al.  Long-circulating and target-specific nanoparticles: theory to practice. , 2001, Pharmacological reviews.

[16]  R. Reilly,et al.  111In-Labeled Trastuzumab (Herceptin) Modified with Nuclear Localization Sequences (NLS): An Auger Electron-Emitting Radiotherapeutic Agent for HER2/neu-Amplified Breast Cancer , 2007, Journal of Nuclear Medicine.

[17]  Jayanth Panyam,et al.  Dynamics of Endocytosis and Exocytosis of Poly(D,L-Lactide-co-Glycolide) Nanoparticles in Vascular Smooth Muscle Cells , 2003, Pharmaceutical Research.

[18]  Bryan Hoang,et al.  Noninvasive monitoring of the fate of 111In-labeled block copolymer micelles by high resolution and high sensitivity microSPECT/CT imaging. , 2009, Molecular pharmaceutics.

[19]  C. Allen,et al.  Formulation of drugs in block copolymer micelles: drug loading and release. , 2006, Current pharmaceutical design.

[20]  Norased Nasongkla,et al.  Functionalized Micellar Systems for Cancer Targeted Drug Delivery , 2007, Pharmaceutical Research.

[21]  R. Reilly,et al.  Multifunctional block copolymer micelles for the delivery of 111In to EGFR-positive breast cancer cells for targeted Auger electron radiotherapy. , 2009, Molecular pharmaceutics.

[22]  W. Pitt,et al.  Drug delivery in polymeric micelles: from in vitro to in vivo. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[23]  T. Park,et al.  Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA-PEG block copolymer. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[24]  I. Ellis,et al.  Clinical Value of Epidermal Growth Factor Receptor Expression in Primary Breast Cancer , 2005, Advances in anatomic pathology.

[25]  N. Nishiyama,et al.  In vivo antitumor activity of the folate-conjugated pH-sensitive polymeric micelle selectively releasing adriamycin in the intracellular acidic compartments. , 2007, Bioconjugate chemistry.

[26]  J. Mendelsohn.  The epidermal growth factor receptor as a target for cancer therapy. , 2001, Endocrine-Related Cancer.

[27]  You Han Bae,et al.  Polymeric micelle for tumor pH and folate-mediated targeting. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[28]  Jasmina Lovrić,et al.  Fate of micelles and quantum dots in cells. , 2007, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[29]  R. Gurny,et al.  Biodegradable nanoparticles for direct or two-step tumor immunotargeting. , 2006, Bioconjugate chemistry.

[30]  R. Reilly,et al.  Apoptotic epidermal growth factor (EGF)-conjugated block copolymer micelles as a nanotechnology platform for targeted combination therapy. , 2007, Molecular pharmaceutics.

[31]  N. Normanno,et al.  Epidermal growth factor-related peptides and their receptors in human malignancies. , 1995, Critical reviews in oncology/hematology.

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

[33]  J. Pollard,et al.  A Paracrine Loop between Tumor Cells and Macrophages Is Required for Tumor Cell Migration in Mammary Tumors , 2004, Cancer Research.

[34]  Bart Cornelissen,et al.  Associations between the uptake of 111In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[35]  G. Bendas,et al.  VCAM-1 directed immunoliposomes selectively target tumor vasculature in vivo. , 2008, Biochimica et biophysica acta.

[36]  E. K. Park,et al.  Preparation and characterization of methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) amphiphilic block copolymeric nanospheres for tumor-specific folate-mediated targeting of anticancer drugs. , 2004, Biomaterials.

[37]  Bethan Psaila,et al.  The metastatic niche: adapting the foreign soil , 2009, Nature Reviews Cancer.

[38]  Tae Gwan Park,et al.  Folate receptor targeted biodegradable polymeric doxorubicin micelles. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[39]  Samuel Zalipsky,et al.  In vivo fate of folate-targeted polyethylene-glycol liposomes in tumor-bearing mice. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[40]  C. Mamot,et al.  Epidermal growth factor receptor-targeted immunoliposomes significantly enhance the efficacy of multiple anticancer drugs in vivo. , 2005, Cancer research.

[41]  M. Dewhirst,et al.  Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. , 2006, Journal of the National Cancer Institute.

[42]  Kazunori Kataoka,et al.  Intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) block copolymers. , 2009, Advanced drug delivery reviews.

[43]  I. Tannock,et al.  Drug penetration in solid tumours , 2006, Nature Reviews Cancer.

[44]  R. Jain,et al.  Oncotic pressure in solid tumors is elevated. , 2000, Cancer research.

[45]  V. Torchilin.  Recent advances with liposomes as pharmaceutical carriers , 2005, Nature Reviews Drug Discovery.

[46]  H. Maeda,et al.  Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[47]  C. de Lange Davies,et al.  Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx™) in human osteosarcoma xenografts , 2005, British Journal of Cancer.

[48]  K. Kataoka,et al.  Preclinical and clinical studies of anticancer agent‐incorporating polymer micelles , 2009, Cancer science.

[49]  Yi Yan Yang,et al.  Incorporation and in vitro release of doxorubicin in thermally sensitive micelles made from poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)-b-poly(D,L-lactide-co-glycolide) with varying compositions. , 2005, Biomaterials.

[50]  J. Mattison,et al.  Expression and biosynthetic variation of the epidermal growth factor receptor in human hepatocellular carcinoma-derived cell lines , 1988, Molecular and cellular biology.

[51]  U. Nielsen,et al.  Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. , 2006, Cancer research.

[52]  E. Rowinsky.  The erbB family: targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. , 2004, Annual review of medicine.