The efficacy of cancer drugs is often limited because only a small fraction of the administered dose accumulates in tumors. Here we report an injectable nanoparticle generator (iNPG) that overcomes multiple biological barriers to cancer drug delivery. The iNPG is a discoidal micrometer-sized particle that can be loaded with chemotherapeutics. We conjugate doxorubicin to poly(L-glutamic acid) by means of a pH-sensitive cleavable linker, and load the polymeric drug (pDox) into iNPG to assemble iNPG-pDox. Once released from iNPG, pDox spontaneously forms nanometer-sized particles in aqueous solution. Intravenously injected iNPG-pDox accumulates at tumors due to natural tropism and enhanced vascular dynamics and releases pDox nanoparticles that are internalized by tumor cells. Intracellularly, pDox nanoparticles are transported to the perinuclear region and cleaved into Dox, thereby avoiding excretion by drug efflux pumps. Compared to its individual components or current therapeutic formulations, iNPG-pDox shows enhanced efficacy in MDA-MB-231 and 4T1 mouse models of metastatic breast cancer, including functional cures in 40–50% of treated mice.

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  1. 1.

    , & Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941–951 (2015).

  2. 2.

    Frontiers in cancer nanomedicine: directing mass transport through biological barriers. Trends Biotechnol. 28, 181–188 (2010).

  3. 3.

    , , & What does physics have to do with cancer? Nat. Rev. Cancer 11, 657–670 (2011).

  4. 4.

    et al. Safety and efficacy of pegylated liposomal doxorubicin-based adjuvant chemotherapy in patients with stage I-III triple-negative breast cancer. Anticancer Res. 34, 7319–7326 (2014).

  5. 5.

    , , , & Metastatic breast cancer: the role of pegylated liposomal doxorubicin after conventional anthracyclines. Cancer Treat. Rev. 34, 391–406 (2008).

  6. 6.

    & Serum-mediated recognition of liposomes by phagocytic cells of the reticuloendothelial system—the concept of tissue specificity. Adv. Drug Deliv. Rev. 32, 45–60 (1998).

  7. 7.

    et al. Size and shape effects in the biodistribution of intravascularly injected particles. J. Control. Release 141, 320–327 (2010).

  8. 8.

    et al. Nanoparticle adhesion to the cell membrane and its effect on nanoparticle uptake efficiency. J. Am. Chem. Soc. 135, 1438–1444 (2013).

  9. 9.

    , & Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer 2, 48–58 (2002).

  10. 10.

    et al. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2, 751–760 (2007).

  11. 11.

    et al. Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications. Nat. Nanotechnol. 3, 151–157 (2008).

  12. 12.

    , , & Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. Angew. Chem. Int. Edn Engl. 42, 4640–4643 (2003).

  13. 13.

    pH Homeostasis of cellular organelles. News Physiol. Sci. 17, 1–5 (2002).

  14. 14.

    et al. Quantitative imaging of endosome acidification and single retrovirus fusion with distinct pools of early endosomes. Proc. Natl. Acad. Sci. USA 109, 17627–17632 (2012).

  15. 15.

    , , & Intravascular delivery of particulate systems: does geometry really matter? Pharm. Res. 26, 235–243 (2009).

  16. 16.

    et al. Discoidal porous silicon particles: fabrication and biodistribution in breast cancer bearing mice. Adv. Funct. Mater. 22, 4225–4235 (2012).

  17. 17.

    et al. Rapid tumoritropic accumulation of systemically injected plateloid particles and their biodistribution. J. Control. Release 158, 148–155 (2012).

  18. 18.

    , & The relevance of tumour pH to the treatment of malignant disease. Radiother. Oncol. 2, 343–366 (1984).

  19. 19.

    et al. Risk factors for doxorubicin-induced congestive heart failure. Ann. Intern. Med. 91, 710–717 (1979).

  20. 20.

    et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat. Med. 18, 1639–1642 (2012).

  21. 21.

    & Mechanisms of multidrug resistance: the potential role of microtubule-stabilizing agents. Ann. Oncol. 18 (suppl. 5), v3–v8 (2007).

  22. 22.

    The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv. Enzyme Regul. 41, 189–207 (2001).

  23. 23.

    Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity. Adv. Drug Deliv. Rev. 91, 3–6 (2015).

  24. 24.

    et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J. Clin. Oncol. 26, 1275–1281 (2008).

  25. 25.

    et al. Cooperative, nanoparticle-enabled thermal therapy of breast cancer. Adv. Healthc. Mater. 1, 84–89 (2012).

  26. 26.

    , , , & HPLC quantification of doxorubicin in plasma and tissues of rats treated with doxorubicin loaded poly(alkylcyanoacrylate) nanoparticles. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 887–888, 128–132 (2012).

  27. 27.

    et al. Breast cancer metastasis suppressor 1 up-regulates miR-146, which suppresses breast cancer metastasis. Cancer Res. 69, 1279–1283 (2009).

  28. 28.

    & Efficient acquisition of dual metastasis organotropism to bone and lung through stable spontaneous fusion between MDA-MB-231 variants. Proc. Natl. Acad. Sci. USA 106, 9385–9390 (2009).

  29. 29.

    et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005).

  30. 30.

    et al. Enhanced gene delivery in porcine vasculature tissue following incorporation of adeno-associated virus nanoparticles into porous silicon microparticles. J. Control. Release 194, 113–121 (2014).

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M.F. is grateful for the Ernest Cockrell Jr. Distinguished Endowed Chair in the Department of Nanomedicine at the Houston Methodist Research Institute. The authors acknowledge financial support from Department of Defense grants W81XWH-09-1-0212 and W81XWH-12-1-0414, National Institute of Health grants NIH U54CA143837, U54CA151668 (M.F.) and 1R01CA193880-01A1 (H.S.), Welch Foundation grant AU-1714 (J.L.), and National Natural Science Foundation of China 81301314 (R.X.). The authors thank the Nanofabrication Core of the Houston Methodist Research Institute for porous silicon microparticle fabrication and surface chemical modification. We acknowledge J. Gu for AFM analysis, D. Kirui for intravital microscopy, and H.H. Hoang for manuscript proofreading and editing.

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Author notes

    • Xiaoyong Deng
    •  & Yu Huang

    Present addresses: Institute of Nanochemistry and Nanobiology, Shanghai University, Shanghai, China (X.D.) and Biomedical Engineering Department, University of South Dakota, Sioux Falls, South Dakota, USA (Y.H.).

    • Rong Xu
    • , Guodong Zhang
    • , Junhua Mai
    •  & Xiaoyong Deng

    These authors contributed equally to this work.


  1. Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.

    • Rong Xu
    • , Guodong Zhang
    • , Junhua Mai
    • , Xiaoyong Deng
    • , Victor Segura-Ibarra
    • , Suhong Wu
    • , Jianliang Shen
    • , Haoran Liu
    • , Zhenhua Hu
    • , Lingxiao Chen
    • , Yi Huang
    • , Eugene Koay
    • , Yu Huang
    • , Elvin Blanco
    • , Xuewu Liu
    • , Mauro Ferrari
    •  & Haifa Shen
  2. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

    • Rong Xu
  3. Division of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Eugene Koay
  4. Department of Pathology and Laboratory Medicine, The University of Texas-Houston Medical School, Houston, Texas, USA.

    • Jun Liu
  5. Houston Methodist Cancer Center, Houston, Texas, USA.

    • Joe E Ensor
  6. Department of Medicine, Weill Cornell Medical College, New York, New York, USA.

    • Mauro Ferrari
  7. Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, USA.

    • Haifa Shen


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M.F. and H.S. developed the concept and supervised experiments. H.S., E.B. and M.F. prepared the manuscript with assistance from R.X., G.Z., X.D.; J.M., X.L. and Y.H. fabricated porous silicon particles. G.Z. and Z.H. synthesized pDox. G.Z., V.S.-I., S.W. and J.L. characterized iNPG-pDox. R.X., J.M., X.D., Z.H., J.S., Y.H., H.L., L.C. and E.K. performed in vivo biological analyses. J.E.E. performed biostatistical analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Mauro Ferrari or Haifa Shen.

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