Overcoming Limitations in Nanoparticle Drug Delivery: Triggered, Intravascular Release to Improve Drug Penetration into Tumors

Overview

Journal Cancer Res

Specialty Oncology

Date 2012 Sep 7

PMID 22952218

Citations 165

Authors

Ashley A Manzoor

Lars H Lindner

Chelsea D Landon

Ji-Young Park

Andrew J Simnick

Matthew R Dreher

Shiva Das

Gabi Hanna

Won Park

Ashutosh Chilkoti

Gerben A Koning

Timo L M Ten Hagen

David Needham

Mark W Dewhirst

Affiliations

Soon will be listed here.

Abstract

Traditionally, the goal of nanoparticle-based chemotherapy has been to decrease normal tissue toxicity by improving drug specificity to tumors. The enhanced permeability and retention effect can permit passive accumulation into tumor interstitium. However, suboptimal delivery is achieved with most nanoparticles because of heterogeneities of vascular permeability, which limits nanoparticle penetration. Furthermore, slow drug release limits bioavailability. We developed a fast drug-releasing liposome triggered by local heat that has already shown substantial antitumor efficacy and is in human trials. Here, we show that thermally sensitive liposomes (Dox-TSL) release doxorubicin inside the tumor vasculature. Real-time confocal imaging of doxorubicin delivery to murine tumors in window chambers and histologic analysis of flank tumors illustrates that intravascular drug release increases free drug in the interstitial space. This increases both the time that tumor cells are exposed to maximum drug levels and the drug penetration distance, compared with free drug or traditional pegylated liposomes. These improvements in drug bioavailability establish a new paradigm in drug delivery: rapidly triggered drug release in the tumor bloodstream.

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References

Issels R, Lindner L, Verweij J, Wust P, Reichardt P, Schem B . Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol. 2010; 11(6):561-70. PMC: 3517819. DOI: 10.1016/S1470-2045(10)70071-1. View

Kong G, Braun R, Dewhirst M . Characterization of the effect of hyperthermia on nanoparticle extravasation from tumor vasculature. Cancer Res. 2001; 61(7):3027-32. View

Weinstein J, Magin R, Yatvin M, ZAHARKO D . Liposomes and local hyperthermia: selective delivery of methotrexate to heated tumors. Science. 1979; 204(4389):188-91. DOI: 10.1126/science.432641. View

Yarmolenko P, Zhao Y, Landon C, Spasojevic I, Yuan F, Needham D . Comparative effects of thermosensitive doxorubicin-containing liposomes and hyperthermia in human and murine tumours. Int J Hyperthermia. 2010; 26(5):485-98. PMC: 2956508. DOI: 10.3109/02656731003789284. View

Weinstein J, Magin R, Cysyk R, ZAHARKO D . Treatment of solid L1210 murine tumors with local hyperthermia and temperature-sensitive liposomes containing methotrexate. Cancer Res. 1980; 40(5):1388-95. View

Schlemmer M, Wendtner C, Lindner L, Abdel-Rahman S, Hiddemann W, Issels R . Thermochemotherapy in patients with extremity high-risk soft tissue sarcomas (HR-STS). Int J Hyperthermia. 2010; 26(2):127-35. DOI: 10.3109/02656730903335995. View

Allen T . Liposomal drug formulations. Rationale for development and what we can expect for the future. Drugs. 1998; 56(5):747-56. DOI: 10.2165/00003495-199856050-00001. View

Needham D, Anyarambhatla G, Kong G, Dewhirst M . A new temperature-sensitive liposome for use with mild hyperthermia: characterization and testing in a human tumor xenograft model. Cancer Res. 2000; 60(5):1197-201. View

Cardenas-Navia L, Secomb T, Dewhirst M . Effects of fluctuating oxygenation on tirapazamine efficacy: Theoretical predictions. Int J Radiat Oncol Biol Phys. 2007; 67(2):581-6. DOI: 10.1016/j.ijrobp.2006.10.002. View

10.

Kabanov A, Batrakova E, Alakhov V . Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery. J Control Release. 2002; 82(2-3):189-212. DOI: 10.1016/s0168-3659(02)00009-3. View

11.

Maeda H, Sawa T, Konno T . Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS. J Control Release. 2001; 74(1-3):47-61. DOI: 10.1016/s0168-3659(01)00309-1. View

12.

Secomb T . A mathematical model for comparison of bolus injection, continuous infusion, and liposomal delivery of doxorubicin to tumor cells. Neoplasia. 2000; 2(4):325-38. PMC: 1550297. DOI: 10.1038/sj.neo.7900096. View

13.

Kong G, Anyarambhatla G, Petros W, Braun R, COLVIN O, Needham D . Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release. Cancer Res. 2001; 60(24):6950-7. View

14.

Dvorak H, Nagy J, Dvorak J, Dvorak A . Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am J Pathol. 1988; 133(1):95-109. PMC: 1880651. View

15.

Johansen P . Doxorubicin pharmacokinetics after intravenous and intraperitoneal administration in the nude mouse. Cancer Chemother Pharmacol. 1981; 5(4):267-70. DOI: 10.1007/BF00434396. View

16.

Minchinton A, Tannock I . Drug penetration in solid tumours. Nat Rev Cancer. 2006; 6(8):583-92. DOI: 10.1038/nrc1893. View

17.

Dewhirst M, Prosnitz L, Thrall D, Prescott D, Clegg S, Charles C . Hyperthermic treatment of malignant diseases: current status and a view toward the future. Semin Oncol. 1998; 24(6):616-25. View

18.

Gaber M, Wu N, Hong K, Huang S, Dewhirst M, Papahadjopoulos D . Thermosensitive liposomes: extravasation and release of contents in tumor microvascular networks. Int J Radiat Oncol Biol Phys. 1996; 36(5):1177-87. DOI: 10.1016/s0360-3016(96)00389-6. View

19.

Seynhaeve A, Hoving S, Schipper D, Vermeulen C, de Wiel-Ambagtsheer G, van Tiel S . Tumor necrosis factor alpha mediates homogeneous distribution of liposomes in murine melanoma that contributes to a better tumor response. Cancer Res. 2007; 67(19):9455-62. DOI: 10.1158/0008-5472.CAN-07-1599. View

20.

West C, Cooper R, Loncaster J, Wilks D, Bromley M . Tumor vascularity: a histological measure of angiogenesis and hypoxia. Cancer Res. 2001; 61(7):2907-10. View