Calcium Bisphosphonate Nanoparticles with Chelator-Free Radiolabeling to Deplete Tumor-Associated Macrophages for Enhanced Cancer Radioisotope Therapy.

Tumor-associated macrophages (TAMs) are often related with poor prognosis after radiotherapy. Depleting TAMs may thus be a promising method to improve the radio-therapeutic efficacy. Herein, we report a biocompatible and biodegradable nanoplatform based on calcium bisphosphonate (CaBP-PEG) nanoparticles for chelator-free radiolabeling chemistry, effective in vivo depletion of TAMs, and imaging-guided enhanced cancer radioisotope therapy (RIT). It is found that CaBP-PEG nanoparticles prepared via a mineralization method with poly(ethylene glycol) (PEG) coating could be labeled with various radioisotopes upon simple mixing, including gamma-emitting 99mTc for single-photon-emission computed tomography (SPECT) imaging, as well as beta-emitting 32P as a therapeutic radioisotope for RIT. Upon intravenous injection, CaBP(99mTc)-PEG nanoparticles exhibit efficient tumor homing, as evidenced by SPECT imaging. Owning to the function of bisphosphonates as clinical drugs to deplete TAMs, suppressed angiogenesis, normalized tumor vasculatures, enhanced intratumoral perfusion, and relieved tumor hypoxia are observed after TAM depletion induced by CaBP-PEG. Such modulated tumor microenvironment appears to be highly favorable for cancer RIT using CaBP(32P)-PEG as the radio-therapeutic agent, which offers excellent synergistic therapeutic effect in inhibiting the tumor growth. With great biocompatibility and multifunctionalities, such CaBP-PEG nanoparticles constituted by Ca2+ and a clinical drug would be rather attractive for clinical translation.

[1]  Meng Qiu,et al.  Omnipotent phosphorene: a next-generation, two-dimensional nanoplatform for multidisciplinary biomedical applications. , 2018, Chemical Society reviews.

[2]  Feng Xing,et al.  Novel concept of the smart NIR-light–controlled drug release of black phosphorus nanostructure for cancer therapy , 2018, Proceedings of the National Academy of Sciences.

[3]  H. Okamura,et al.  Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug , 2017, Scientific Reports.

[4]  Miles A. Miller,et al.  Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts , 2017, Science Translational Medicine.

[5]  Song Shen,et al.  Spatial Targeting of Tumor-Associated Macrophages and Tumor Cells with a pH-Sensitive Cluster Nanocarrier for Cancer Chemoimmunotherapy. , 2017, Nano letters.

[6]  Heather H Gustafson,et al.  Progress in tumor-associated macrophage (TAM)-targeted therapeutics. , 2017, Advanced drug delivery reviews.

[7]  Zhihong Chen,et al.  Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma. , 2017, Cancer research.

[8]  Alberto Mantovani,et al.  Tumour-associated macrophages as treatment targets in oncology , 2017, Nature Reviews Clinical Oncology.

[9]  J. Ji,et al.  Dual Enzymatic Reaction-Assisted Gemcitabine Delivery Systems for Programmed Pancreatic Cancer Therapy. , 2017, ACS nano.

[10]  Kai Yang,et al.  Radionuclide I-131 Labeled Albumin-Paclitaxel Nanoparticles for Synergistic Combined Chemo-radioisotope Therapy of Cancer , 2017, Theranostics.

[11]  Liangzhu Feng,et al.  CaCO3 nanoparticles as an ultra-sensitive tumor-pH-responsive nanoplatform enabling real-time drug release monitoring and cancer combination therapy. , 2016, Biomaterials.

[12]  K. M. Au,et al.  Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic. , 2016, Biomaterials.

[13]  D. Ribatti,et al.  A novel liposomal Clodronate depletes tumor-associated macrophages in primary and metastatic melanoma: Anti-angiogenic and anti-tumor effects. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[14]  Li Wang,et al.  High Infiltration of Tumor-Associated Macrophages Influences Poor Prognosis in Human Gastric Cancer Patients, Associates With the Phenomenon of EMT , 2016, Medicine.

[15]  Kai Yang,et al.  Polydopamine as a Biocompatible Multifunctional Nanocarrier for Combined Radioisotope Therapy and Chemotherapy of Cancer , 2015 .

[16]  D. Argyle,et al.  Tumour-associated macrophages are associated with vascular endothelial growth factor expression in canine mammary tumours. , 2015, Veterinary and comparative oncology.

[17]  Kai Yang,et al.  Imaging‐Guided Combined Photothermal and Radiotherapy to Treat Subcutaneous and Metastatic Tumors Using Iodine‐131‐Doped Copper Sulfide Nanoparticles , 2015 .

[18]  Kevin J. Harrington,et al.  The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence , 2015, Nature Reviews Cancer.

[19]  Liangzhu Feng,et al.  Drug-Induced Self-Assembly of Modified Albumins as Nano-theranostics for Tumor-Targeted Combination Therapy. , 2015, ACS nano.

[20]  Yuntian Shen,et al.  Research progress of relationship between tumor microenvironment and radioresistance , 2015 .

[21]  Naveid A Ali,et al.  Real-time intravital imaging establishes tumor-associated macrophages as the extraskeletal target of bisphosphonate action in cancer. , 2015, Cancer discovery.

[22]  N. Itano,et al.  Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment , 2014, Cancers.

[23]  Xing Guo,et al.  Redox-responsive polyanhydride micelles for cancer therapy. , 2014, Biomaterials.

[24]  J. Russell,et al.  The irradiated tumor microenvironment: role of tumor-associated macrophages in vascular recovery , 2013, Front. Physiol..

[25]  R. Jain,et al.  Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. , 2013, Cancer research.

[26]  C. Lewis,et al.  Macrophage delivery of an oncolytic virus abolishes tumor regrowth and metastasis after chemotherapy or irradiation. , 2013, Cancer research.

[27]  I. Holen,et al.  Tumour macrophages as potential targets of bisphosphonates , 2011, Journal of Translational Medicine.

[28]  L. Su,et al.  Tumor-associated macrophages mediate immunosuppression in the renal cancer microenvironment by activating the 15-lipoxygenase-2 pathway. , 2011, Cancer research.

[29]  P. Chu,et al.  Hollow chitosan-silica nanospheres as pH-sensitive targeted delivery carriers in breast cancer therapy. , 2011, Biomaterials.

[30]  Ming-Jium Shieh,et al.  Multimodal image-guided photothermal therapy mediated by 188Re-labeled micelles containing a cyanine-type photosensitizer. , 2011, ACS nano.

[31]  Wei Zhang,et al.  Expression of tumor-associated macrophages and vascular endothelial growth factor correlates with poor prognosis of peripheral T-cell lymphoma, not otherwise specified , 2011, Leukemia & lymphoma.

[32]  Yu-cheng Tseng,et al.  Biodegradable calcium phosphate nanoparticle with lipid coating for systemic siRNA delivery. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[33]  M. Barcellos-Hoff,et al.  EDITORIAL: Resistance to radio- and chemotherapy and the tumour microenvironment , 2009, International journal of radiation biology.

[34]  Ting-Kai Chang,et al.  Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation. , 2009, Journal of the American Chemical Society.

[35]  Tracy T Batchelor,et al.  AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. , 2007, Cancer cell.

[36]  H. Saji,et al.  Development of a novel 99mTc-chelate-conjugated bisphosphonate with high affinity for bone as a bone scintigraphic agent. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[37]  R. Schwendener,et al.  Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach , 2006, British Journal of Cancer.

[38]  J. Pollard,et al.  Distinct role of macrophages in different tumor microenvironments. , 2006, Cancer research.

[39]  H. Gest.  The early history of 32P as a radioactive tracer in biochemical research: A personal memoir , 2005, Biochemistry and molecular biology education : a bimonthly publication of the International Union of Biochemistry and Molecular Biology.

[40]  S. Adelstein,et al.  Radiobiologic principles in radionuclide therapy. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[41]  L. To,et al.  The Nitrogen‐Containing Bisphosphonate, Zoledronic Acid, Influences RANKL Expression in Human Osteoblast‐Like Cells by Activating TNF‐α Converting Enzyme (TACE) , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[42]  Damon L. Meyer,et al.  Comparison of anti-CD20 and anti-CD45 antibodies for conventional and pretargeted radioimmunotherapy of B-cell lymphomas. , 2003, Blood.

[43]  Torgny Stigbrand,et al.  Tumour therapy with radionuclides: assessment of progress and problems. , 2003, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[44]  John E Tomaszewski,et al.  Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era , 2002, Cancer.

[45]  A. Mcewan.  Radioisotope therapy and clinical trial design: the need for consensus and innovation. , 2002, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[46]  N. Jonjić,et al.  Correlation between vascular endothelial growth factor, angiogenesis, and tumor-associated macrophages in invasive ductal breast carcinoma , 2002, Virchows Archiv.

[47]  C. Hoefnagel.  Radionuclide cancer therapy , 1998, Annals of nuclear medicine.

[48]  D. Brenner,et al.  The biological effectiveness of radon-progeny alpha particles. II. Oncogenic transformation as a function of linear energy transfer. , 1995, Radiation research.

[49]  C. L. D. Ligny,et al.  Determination of the oxidation state of Tc in 99Tc(Sn)EHDP, 99mTc(Sn)EHDP, 99Tc(Sn)MDP and 99mTc(Sn)MDP complexes. Characterization of Tc(III)-, Tc(IV)- and Tc(V)EHDP complexes , 1990 .

[50]  Okulov Vb,et al.  The role of macrophages in tumor growth , 1990 .

[51]  R. Gupta,et al.  32P-postlabeling test for covalent DNA binding of chemicals in vivo: application to a variety of aromatic carcinogens and methylating agents. , 1984, Carcinogenesis.

[52]  R. A. Holmes,et al.  Assay of 32P-sodium phosphate using a commercial dose calibrator. , 1976, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[53]  G. Stent,et al.  Stabilization to 32P decay and onset of DNA replication of T4 bacteriophage. , 1961, Journal of molecular biology.