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

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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.

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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

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ACKNOWLEDGEMENTS

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

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Authors and Affiliations

  1. Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854-8020, USA

    Pooja Chandna, Jayant J. Khandare, Elizabeth Ber & Tamara Minko

  2. The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey, 08903, USA

    Lorna Rodriguez-Rodriguez & Tamara Minko

  3. Department of Obstetrics and Gynecology, UMDNJ/Robert Wood Johnson Medical School, 125 Paterson Street, New Brunswick, New Jersey, 08901, USA

    Lorna Rodriguez-Rodriguez

Authors
  1. Pooja Chandna
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  2. Jayant J. Khandare
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  3. Elizabeth Ber
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  4. Lorna Rodriguez-Rodriguez
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  5. Tamara Minko
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Correspondence to Tamara Minko.

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Chandna, P., Khandare, J.J., Ber, E. et al. Multifunctional Tumor-Targeted Polymer-Peptide-Drug Delivery System for Treatment of Primary and Metastatic Cancers. Pharm Res 27, 2296–2306 (2010). https://doi.org/10.1007/s11095-010-0235-2

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  • DOI: https://doi.org/10.1007/s11095-010-0235-2

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