Skip to main content
SpringerLink
Log in

Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT)

  • Research Paper
  • Published:
Journal of Nanoparticle Research Aims and scope Submit manuscript

Abstract

The pharmacokinetics (PK) of carrier-mediated agents (CMA) is dependent upon the carrier system. As a result, CMA PK differs greatly from the PK of small molecule (SM) drugs. Advantages of CMAs over SMs include prolonged circulation time in plasma, increased delivery to tumors, increased antitumor response, and decreased toxicity. In theory, CMAs provide greater tumor drug delivery than SMs due to their prolonged plasma circulation time. We sought to create a novel PK metric to evaluate the efficiency of tumor and tissue delivery of CMAs and SMs. We conducted a study evaluating the plasma, tumor, liver, and spleen PK of CMAs and SMs in mice bearing subcutaneous flank tumors using standard PK parameters and a novel PK metric entitled relative distribution over time (RDI-OT), which measures efficiency of delivery. RDI-OT is defined as the ratio of tissue drug concentration to plasma drug concentration at each time point. The standard concentration versus time area under the curve values (AUC) of CMAs were higher in all tissues and plasma compared with SMs. However, 8 of 17 SMs had greater tumor RDI-OT AUC0–last values than their CMA comparators and all SMs had greater tumor RDI-OT AUC0–6 h values than their CMA comparators. Our results indicate that in mice bearing flank tumor xenografts, SMs distribute into tumor more efficiently than CMAs. Further research in additional tumor models that may more closely resemble tumors seen in patients is needed to determine if our results are consistent in different model systems.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Alakhov V, Klinski E, Li S, Pietrzynski G, Venne A, Batrakova E et al (1999) Block copolymer-based formulation of doxorubicin. From cell screen to clinical trials. Colloids Surf B 16:113–134

    Article  Google Scholar 

  • Alonso MJ (2004) Nanomedicines for overcoming biological barriers. Biomed Pharmacother 58:168–172

    Article  Google Scholar 

  • Caron WP, Song G, Kumar P, Rawal S, Zamboni WC (2012) Interpatient pharmacokinetic and pharmacodynamic variability of carrier-mediated anticancer agents. Clin Pharmacol Ther 91:802–812

    Article  Google Scholar 

  • Chu KS, Hasan W, Rawal S, Walsh MD, Enlow EM et al (2013) Plasma, tumor and tissue pharmacokinetics of docetaxel delivered via nanoparticles of different sizes and shapes in mice bearing SKOV-3 human ovarian carcinoma xenograft. Nanomedicine 9:686–693

    Article  Google Scholar 

  • Combest AJ, Roberts PJ, Dillon PM, Sandison K, Hanna SK et al (2012) Genetically engineered cancer models, but not xenografts, faithfully predict anticancer drug exposure in melanoma tumors. Oncologist 17:1303–1316

    Article  Google Scholar 

  • Desjardins JP, Abbott EA, Emerson DL, Tomkinson BE, Leray JD, Brown EN et al (2001) Biodistribution of NX211, liposomal lurtotecan, in tumor-bearing mice. Anticancer Drugs 12:235–245

    Article  Google Scholar 

  • Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D (1999) Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev 51:691–743

    Google Scholar 

  • Duncan R (1999) Polymer conjugates for tumour targeting and intracytoplasmic delivery. The EPR effect as a common gateway? Pharm Sci Technol Today 2:441–449

    Article  Google Scholar 

  • Farrell NP (2011) Platinum formulations as anticancer drugs clinical and pre-clinical studies. Curr Top Med Chem 11:2623–2631

    Article  Google Scholar 

  • Feng L, Benhabbour SR, Mumper RJ (2013) Oil-filled lipid nanoparticles containing 2′-(2-bromohexadecanoyl)-docetaxel for the treatment of breast cancer. Adv Healthc Mater 2:1451–1457

    Article  Google Scholar 

  • Forssen EA, Coulter DM, Proffitt RT (1992) Selective in vivo localization of daunorubicin small unilamellar vesicles in solid tumors. Cancer Res 52:3255–3261

    Google Scholar 

  • Gabizon Goren D, Horowitz T, Tzemach A, Losos A, Siegal T et al (1997) Long-circulating liposomes for drug delivery in cancer therapy: a review of biodistribution studies in tumor-bearing animals. Adv Drug Deliv Rev 24:337–344

    Article  Google Scholar 

  • Ge Y, Tiwari A, Li S (2011) Nanomedicine—bridging the gap between nanotechnology and medicine. Adv Mat Lett 2:1–2

    Article  Google Scholar 

  • Hennenfent KL, Govindan R (2006) Novel formulations of taxanes: a review. Old wine in a new bottle? Ann Oncol 17:735–749

    Article  Google Scholar 

  • Konishi H, Takagi A, Kurita A, Kaneda N, Matsuzaki T (2012) PEGylated liposome IHL-305 markedly improved the survival of ovarian cancer peritoneal metastasis in mouse. BMC Cancer 12:462

    Article  Google Scholar 

  • Laverman P, Carstens MG, Boerman OC, Dams ET, Oyen WJ, van Rooijen N, Corstens FH, Storm G (2001) Factors affecting the accelerated blood clearance of polyethylene glycol-liposomes upon repeated injection. J Pharmacol Exp Ther 298:607–612

    Google Scholar 

  • Litzinger DC, Buiting AM, van Rooijen N, Huang L (1994) Effect of liposome size on the circulation time and intraorgan distribution of amphipathic poly(ethylene glycol)-containing liposomes. Biochim Biophys Acta 1190:99–107

    Article  Google Scholar 

  • Ma P, Rahima Benhabbour S, Feng L, Mumper RJ (2013) 2′-Behenoyl-paclitaxel conjugate containing lipid nanoparticles for the treatment of metastatic breast cancer. Cancer Lett 334:253–262

    Article  Google Scholar 

  • Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46:6387–6392

    Google Scholar 

  • Mayer LD, Bally MB, Cullis PR, Wilson SL, Emerman JT (1990) Comparison of free and liposome encapsulated doxorubicin tumor drug uptake and antitumor efficacy in the SC115 murine mammary tumor. Cancer Lett 53:183–190

    Article  Google Scholar 

  • Oberoi HS, Nukolova NV, Laquer FC, Poluektova LY, Huang J et al (2012) Cisplatin-loaded core cross-linked micelles: comparative pharmacokinetics, antitumor activity, and toxicity in mice. Int J Nanomedicine 7:2557–2571

    Article  Google Scholar 

  • Papahadjopoulos D, Allen TM, Gabizon A, Mayhew E, Matthay K, Huang SK, Lee KD, Woodle MC, Lasic DD, Redemann C et al (1991) Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci USA 88:11460–11464

    Article  Google Scholar 

  • Sapra P, Zhao H, Mehlig M, Malaby J, Kraft P, Longley C et al (2008) Novel delivery of SN38 markedly inhibits tumor growth in xenografts, including a camptothecin-11-refractory model. Clin Cancer Res 14:1888–1896

    Article  Google Scholar 

  • Takahashi A, Ohkohchi N, Yasunaga M, Kuroda J, Koga Y, Kenmotsu H et al (2010) Detailed distribution of NK012, an SN-38-incorporating micelle, in the liver and its potent antitumor effects in mice bearing liver metastases. Clin Cancer Res 16:4822–4831

    Article  Google Scholar 

  • van Zuylen L, Verweij J, Sparreboom A (2001) Role of formulation vehicles in taxane pharmacology. Invest New Drugs 19:125–141

    Article  Google Scholar 

  • Vonarbourg A, Passirani C, Saulnier P, Benoit JP (2006) Parameters influencing the stealthiness of colloidal drug delivery systems. Biomaterials 27:4356–4373

    Article  Google Scholar 

  • Walsh MD, Hanna SK, Sen J, Rawal S, Cabral CB et al (2012) Pharmacokinetics and antitumor efficacy of XMT-1001, a novel, polymeric topoisomerase I inhibitor, in mice bearing HT-29 human colon carcinoma xenografts. Clin Cancer Res 18:2591–2602

    Article  Google Scholar 

  • Zamboni WC (2005) Liposomal, nanoparticle, and conjugated formulations of anticancer agents. Clin Cancer Res 11:8230–8234

    Article  Google Scholar 

  • Zamboni WC (2008) Concept and clinical evaluation of carrier-mediated anticancer agents. Oncologist 13:248–260

    Article  Google Scholar 

  • Zamboni WC, Gervais AC, Egorin MJ, Schellens JH, Zuhowski EG et al (2004) Systemic and tumor disposition of platinum after administration of cisplatin or STEALTH liposomal-cisplatin formulations (SPI-077 and SPI-077 B103) in a preclinical tumor model of melanoma. Cancer Chemother Pharmacol 53:329–336

    Article  Google Scholar 

  • Zamboni WC, Strychor S, Joseph E, Walsh DR, Zamboni BA et al (2007) Plasma, tumor, and tissue disposition of STEALTH liposomal CKD-602 (S-CKD602) and nonliposomal CKD-602 in mice bearing A375 human melanoma xenografts. Clin Cancer Res 13:7217–7223

    Article  Google Scholar 

Download references

Conflict of interest

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number U54CA151652. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill (UNC) Eshelman School of Pharmacy, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC, 27599-7361, USA

    Andrew J. Madden, Sumit Rawal, Katie Sandison, Ryan Schell, Allison Schorzman & William C. Zamboni

  2. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    Allison Deal, Joseph DeSimone & William C. Zamboni

  3. UNC Lineberger Biostatistics Core Facility, University of North Carolina, Chapel Hill, NC, USA

    Allison Deal

  4. Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA

    Lan Feng & Ping Ma

  5. UNC Eshelman School of Pharmacy, University of North Carolina Chapel Hill, Chapel Hill, NC, USA

    Russell Mumper

  6. Department of Pharmaceutical Sciences, University of North Carolina, Chapel Hill, NC, USA

    Joseph DeSimone

  7. Department of Chemistry, University of North Carolina, Chapel Hill, NC, USA

    Joseph DeSimone

  8. Carolina Center of Cancer Nanotechnology Excellence, University of North Carolina, Chapel Hill, NC, USA

    Joseph DeSimone & William C. Zamboni

  9. Department of Pharmacology, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA

    Joseph DeSimone

  10. Institute for Nanomedicine, University of North Carolina, Chapel Hill, NC, USA

    Joseph DeSimone

  11. Institute for Advanced Materials, University of North Carolina, Chapel Hill, NC, USA

    Joseph DeSimone

  12. UNC Institute for Pharmacogenomics and Individualized Therapy, Chapel Hill, NC, USA

    William C. Zamboni

  13. North Carolina Medical Innovation Network, Chapel Hill, NC, USA

    William C. Zamboni

Authors
  1. Andrew J. Madden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sumit Rawal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katie Sandison
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ryan Schell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Allison Schorzman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Allison Deal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lan Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ping Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Russell Mumper
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Joseph DeSimone
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. William C. Zamboni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William C. Zamboni.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 46 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Madden, A.J., Rawal, S., Sandison, K. et al. Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT). J Nanopart Res 16, 2662 (2014). https://doi.org/10.1007/s11051-014-2662-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11051-014-2662-1

Keywords

Search

Navigation