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Pharmaceutical Research

, Volume 27, Issue 11, pp 2296–2306 | Cite as

Multifunctional Tumor-Targeted Polymer-Peptide-Drug Delivery System for Treatment of Primary and Metastatic Cancers

  • Pooja Chandna
  • Jayant J. Khandare
  • Elizabeth Ber
  • Lorna Rodriguez-Rodriguez
  • Tamara Minko
Research Paper

ABSTRACT

Purpose

In order to improve drug delivery to drug-resistant ovarian tumors, we constructed a multifunctional polymer-peptide-drug conjugate (PPDC) system for effective treatment of primary and metastatic ovarian cancers.

Methods

The PPDC consists of the poly(Ethylene Glycol) (PEG) polymeric carrier conjugated via citric acid spacers to anticancer drug (Camptothecin, CPT), tumor targeting moiety (LRHR, a synthetic analog of luteinizing hormone-releasing hormone) and a suppressor of cellular antiapoptotic defense (BH3 peptide). To test the conjugates in vitro and in vivo, cancer cells were isolated from tissue samples obtained from patients with ovarian primary tumor and metastatic malignant ascites.

Results

It was found that cells isolated from malignant ascites were more aggressive in terms of tumor growth and more resistant to chemotherapy when compared with those isolated from primary tumors. PPDC containing two copies of drugs and peptides was most efficient in treatment of primary tumors and intraperitoneal metastases. Multiple treatments with this PPDC led to almost complete regression of primary tumor and prevented growth of malignant ascites.

Conclusion

The proposed multifunctional polymeric delivery system which consists of multiple copies of the drug and peptides demonstrated significantly higher antitumor activity in primary and metastatic cancers when compared with drug alone and PEG-CPT conjugate.

KEY WORDS

BH3 peptide camptothecin LHRH peptide PEG polymer proapoptotic peptide 

ABBREVIATIONS

APAF1

apoptotic protease activating factor 1

BCA

bicinchoninic acid

BH3 Peptide

CL2 Homology 3 Peptide

CA

citric acid

CASP3

Caspase 3

CASP9

Caspase 9

CPT

camptothecin

FITC

fluorescein isothiocyanate

LHRH

luteinizing hormone-releasing hormone

MDR

multidrug resistance

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PEG

poly(Ethylene Glycol)

PPDC

polymer-peptide-drug conjugate

RT-PCR

reverse transcriptase-polymerase chain reaction

β2-m

β2-microglobulin

Notes

ACKNOWLEDGEMENTS

The research was supported in part by NIH Grants CA100098 and CA138533 from the National Cancer Institute.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Pooja Chandna
    • 1
  • Jayant J. Khandare
    • 1
  • Elizabeth Ber
    • 1
  • Lorna Rodriguez-Rodriguez
    • 2
    • 3
  • Tamara Minko
    • 1
    • 2
  1. 1.Department of Pharmaceutics, Ernest Mario School of PharmacyRutgers, The State University of New JerseyPiscatawayUSA
  2. 2.The Cancer Institute of New JerseyNew BrunswickUSA
  3. 3.Department of Obstetrics and GynecologyUMDNJ/Robert Wood Johnson Medical SchoolNew BrunswickUSA

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