Pharmaceutical Research

, Volume 27, Issue 11, pp 2317–2329

Temozolomide Delivery to Tumor Cells by a Multifunctional Nano Vehicle Based on Poly(β-L-malic acid)

  • Rameshwar Patil
  • José Portilla-Arias
  • Hui Ding
  • Satoshi Inoue
  • Bindu Konda
  • Jinwei Hu
  • Kolja A. Wawrowsky
  • Paul K. Shin
  • Keith L. Black
  • Eggehard Holler
  • Julia Y. Ljubimova
Research Paper

DOI: 10.1007/s11095-010-0091-0

Cite this article as:
Patil, R., Portilla-Arias, J., Ding, H. et al. Pharm Res (2010) 27: 2317. doi:10.1007/s11095-010-0091-0

ABSTRACT

Purpose

Temozolomide (TMZ) is a pro-drug releasing a DNA alkylating agent that is the most effective drug to treat glial tumors when combined with radiation. TMZ is toxic, and therapeutic dosages are limited by severe side effects. Targeted delivery is thus needed to improve efficiency and reduce non-tumor tissue toxicity.

Methods

Multifunctional targetable nanoconjugates of TMZ hydrazide were synthesized using poly(β-L-malic acid) platform, which contained a targeting monoclonal antibody to transferrin receptor (TfR), trileucine (LLL), for pH-dependent endosomal membrane disruption, and PEG for protection.

Results

The water-soluble TMZ nanoconjugates had hydrodynamic diameters in the range of 6.5 to 14.8 nm and ζ potentials in the range of −6.3 to −17.7 mV. Fifty percent degradation in human plasma was observed in 40 h at 37°C. TMZ conjugated with polymer had a half-life of 5–7 h, compared with 1.8 h for free TMZ. The strongest reduction of human brain and breast cancer cell viability was obtained by versions of TMZ nanoconjugates containing LLL and anti-TfR antibody. TMZ-resistant cancer cell lines were sensitive to TMZ nanoconjugate treatment.

Conclusions

TMZ-polymer nanoconjugates entered the tumor cells by receptor-mediated endocytosis, effectively reduced cancer cell viability, and can potentially be used for targeted tumor treatment.

KEY WORDS

anti-TfR mAb nanoconjugate pH-dependent membrane disruption polymalic acid targeted drug delivery temozolomide 

ABBREVIATIONS

TMZ

temozolomide

TMZH

temozolomide hydrazide

PMLA

Poly(β-L-malic acid)

HuTfR

anti-human transferrin receptor

mAb

monoclonal antibody

LOEt

L-leucine ethyl ester

LLL

L-leucine tripeptide

Alex680

Alexa Fluor® 680 C2 maleimide

Nanoconjugates are abbreviated as shown in Charts 3 and 4

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Rameshwar Patil
    • 1
  • José Portilla-Arias
    • 1
  • Hui Ding
    • 1
  • Satoshi Inoue
    • 1
  • Bindu Konda
    • 1
  • Jinwei Hu
    • 1
  • Kolja A. Wawrowsky
    • 2
  • Paul K. Shin
    • 3
  • Keith L. Black
    • 1
  • Eggehard Holler
    • 1
    • 4
  • Julia Y. Ljubimova
    • 1
  1. 1.Department of NeurosurgeryCedars-Sinai Medical CenterLos AngelesUSA
  2. 2.Department of MedicineCedars-Sinai Medical CenterLos AngelesUSA
  3. 3.Department of Chemistry and BiochemistryCalifornia State UniversityNorthridgeUSA
  4. 4.Institut für Biophysik und Physikalische Biochemie der Universität RegensburgRegensburgGermany