Abstract 5511: Multifunctional CREKA peptide conjugated lipid nanocarriers of synergistically acting Noscapine and Doxorubicin for breast cancer therapy
Authors: Mahavir B. Chougule, Apurva R. Patel, Ram Patlolla, Mandip Sachdeva
Journal: Cancer Research (2010)

Abstract Estrogen receptor negative (ER−) breast cancers (∼40%) are clinically aggressive with poor clinical outcome. Combination of different mechanism based antimicrotubular Noscapine and DNA intercalating Doxorubicin may lead to additive/synergistic activity against ER− breast cancer. Clinical utility of safer oral Noscapine (poor bioavailability and short half life) and Doxorubicin (cardiotoxicity and myelosuppression) has been limited. Encapsulation of Noscapine and Doxorubicin in nanocarriers whose surface is modified with pegylated CREKA peptide (MNCs) will significantly deliver nanocarriers to tumors by homing to tumor stroma, vessel wall and thereby releasing both drugs in controlled manner to exert anticancer activity. The purpose of this study was to encapsulate synergistically acting Noscapine and Doxorubicin in nanocarrier and modify the nanocarrier surface with CREKA and evaluate for anticancer activity in MDA-MB 231 ER− breast cancer cells. Isobolographic method and TUNEL assay were used to study Noscapine (10, 20 and 30 µM) and Doxorubicin interaction in MDA-MB 231 cells. For preparation of MNCs, Noscapine and Doxorubicin (molar ratio of 1:400) were dissolved in lipophilic phase composed of Miglyol (6% w/v), Compritol (3% w/v) and DOGS-NTA-Ni (0.2 % w/v). Lipophilic phase was poured to aqueous phase containing Polaxamer 188 (1.2 % w/v in water) and subjected to high-pressure homogenization to yield DOGS-NTA-Ni engrafted nanocarriers. Six-Histidine tagged PEG (1K)-CREKA (0.01-0.04 % w/v) was incubated with nanocarriers for 30 min for conjugation of DOGS-NTA-Ni engrafted nanocarrier with Histidine tagged peptide to yield MNCs. MNCs were characterized for size, drug release, antiproliferative and clot binding efficiency. Noscapine and Doxorubicin alone showed IC50 of 42 ± 4 µM and 0.25 ± 0.02 µM against MDA-MB cells respectively. In presence of Noscapine solution (20 µM), the IC50 of Doxorubicin solution was reduced to 0.05 µM (5-fold). Further, the combination Index values (&amp;lt; 0.6) and higher apoptotic cells (P 96 % of encapsulation and controlled release of both drugs (8 hr∼15 % and 48 hr∼ 60 %). A significantly (P &amp;lt; 0.01) higher binding of MNCs (CREKA concentration 0.045 % w/v) to the clotted plasma proteins showed the targeting ability of nanocarriers. MNCs showed similar IC50 values (20 µM Noscapine + 0.05 µM Doxorubicin) to that of solution combination. In conclusion, Noscapine acts synergistically with Doxorubicin and combination delivery of Noscapine and Doxorubicin using nanocarriers conjugated with CREKA showed significant increase in cytotoxicity with controlled drug release and significant binding efficiency. Multifunctional nanocarriers can effectively inhibit breast cancer and may reduce limitations associated with chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5511.