Multifunctional tumor-targeted polymer-peptide-drug delivery system for treatment of primary and metastatic cancers.
OBJECTIVE
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.


CONCLUSIONS
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.
Chandna
Pooja
P
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey 08854-8020, USA.
Khandare
Jayant J
JJ
Ber
Elizabeth
E
Rodriguez-Rodriguez
Lorna
L
Minko
Tamara
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D017209:Apoptosis; D001483:Base Sequence; D017931:DNA Primers; D004337:Drug Carriers; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage*; D011108:Polymers / Q000008:administration & dosage*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D000970:Antineoplastic Agents; D017931:DNA Primers; D004337:Drug Carriers; D010455:Peptides; D011108:Polymers