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Targeted delivery of platinum-taxane combination therapy in ovarian cancer.

ABSTRACT: Biodegradable polypeptide-based nanogels have been developed from amphiphilic block copolymers, poly(ethylene glycol)-b-poly(L-glutamic acid)-b-poly(L-phenylalanine), which effectively co-incorporate cisplatin and paclitaxel, the clinically used drug combination for the treatment of advanced ovarian cancer. In order to target both drugs selectively to the tumor cells, we explored the benefits of ligand-mediated drug delivery by targeting folate receptors, which are overexpressed in most ovarian cancers. Drug-loaded nanogels were surface-functionalized with folic acid (FA) with the help of a PEG spacer without affecting the ligand binding affinity and maintaining the stability of the carrier system. FA-decorated nanogels significantly suppressed the growth of intraperitoneal ovarian tumor xenografts outperforming their nontargeted counterparts without extending their cytotoxicity to the normal tissues. We also confirmed that synchronized co-delivery of the platinum-taxane drug combination via single carrier to the same targeted cells is more advantageous than a combination of targeted single drug formulations administered at the same drug ratio. Lastly, we demonstrated that the same platform can also be used for localized chemotherapy. Our data indicate that intraperitoneal administration can be more effective in the context of targeted combination therapy. Our findings suggest that multifunctional nanogels are promising drug delivery carriers for improvement of current treatment for ovarian cancer.

SUBMITTER: Desale SS

PROVIDER: S-EPMC4688128 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Targeted delivery of platinum-taxane combination therapy in ovarian cancer.

Desale Swapnil S SS Soni Kruti S KS Romanova Svetlana S Cohen Samuel M SM Bronich Tatiana K TK

Journal of controlled release : official journal of the Controlled Release Society 20150914 Pt B

Biodegradable polypeptide-based nanogels have been developed from amphiphilic block copolymers, poly(ethylene glycol)-b-poly(L-glutamic acid)-b-poly(L-phenylalanine), which effectively co-incorporate cisplatin and paclitaxel, the clinically used drug combination for the treatment of advanced ovarian cancer. In order to target both drugs selectively to the tumor cells, we explored the benefits of ligand-mediated drug delivery by targeting folate receptors, which are overexpressed in most ovarian ...[more]

PMID: 26381902

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Project description:Ten human ovarian cancer cell lines were kindly provided as follows: an ovarian serous adenocarcinoma cell line, SKOV3 (Dr. N. Nagai, Hiroshima University, Hiroshima, Japan); KF28 and its TXL/CDDP-resistant variant (Dr. Y. Kikuchi, National Defense Medical College, Saitama, Japan); KF, SHIN3 and 5 ovarian clear cell adenocarcinoma cell lines, KK, TAYA, RMG-1, OVISE and OVTOKO (Dr. M. Suzuki, Jichi Medical School, Tochigi, Japan). All cell lines were cultured in RPMI 1640 medium (Life Technologies, Inc., Grand Island, NY) containing 10% heat-inactivated fetal bovine serum (FBS; BioWhittaker, Verviers, Belgium) in a humidified atmosphere of 5% CO2 and maintained in continuous exponential growth by passage every 3 days. Exponentially growing cultured cells were collected after two-washings with PBS. The cell pellets were immediately frozen in liquid nitrogen, and stored until use. Total RNA was extracted using QIAGEN RNeasy mini kit (QIAGEN, Inc., Valencia, CA). The quality of the RNA was checked using Agilent Technologies 2100 Bioanalyzer (Agilent, Palo Alto, CA). CodeLink Expression Bioarray System (Amersham Bioscience, Tokyo, Japan) was used according to the manufacturer’s protocol. Briefly, first-strand cDNA was generated from 1 microgram of total RNA of each cell line using reverse transcriptase and a T7 primer, and then second-strand cDNA was produced using DNA polymerase mix and RNase H. Complementary RNA (cRNA) was generated via an in vitro transcription reaction using T7 RNA polymerase and biotin-11-UTP (Perkin Elmer, Boston, MA), which was quantified by spectrometry and checked using Agilent Technologies 2100 Bioanalyzer (Agilent). Ten-microgram of cRNA was then fragmented and hybridized to a Uniset Human 20K I Bioarray containing 19,881 probes with positive and negative bacterial control probes. After hybridization, the arrays were rinsed and labeled with Streptavidin-Cy5, scanned using Agilent DNA Microarray Scanner (Agilent), then analyzed with CodeLink Expression Analysis Software ver.2.3. Expression levels were normalized to the median expression value of the whole array spots. Keywords: parallel sample

Project description:Cancer heterogeneity and drug resistance limit the efficacy of cancer therapy. To address this issue, we have developed an integrated treatment protocol for effective treatment of heterogeneous ovarian cancer. Methods: An amphiphilic polymer coated magnetic iron oxide nanoparticle was conjugated with near infrared dye labeled HER2 affibody and chemotherapy drug cisplatin. The effects of the theranostic nanoparticle on targeted drug delivery, therapeutic efficacy, non-invasive magnetic resonance image (MRI)-guided therapy, and optical imaging detection of therapy resistant tumors were examined in an orthotopic human ovarian cancer xenograft model with highly heterogeneous levels of HER2 expression. Results: We found that systemic delivery of HER2-targeted magnetic iron oxide nanoparticles carrying cisplatin significantly inhibited the growth of primary tumor and peritoneal and lung metastases in the ovarian cancer xenograft model in nude mice. Differential delivery of theranostic nanoparticles into individual tumors with heterogeneous levels of HER2 expression and various responses to therapy were detectable by MRI. We further found a stronger therapeutic response in metastatic tumors compared to primary tumors, likely due to a higher level of HER2 expression and a larger number of proliferating cells in metastatic tumor cells. Relatively long-time retention of iron oxide nanoparticles in tumor tissues allowed interrogating the relationship between nanoparticle drug delivery and the presence of resistant residual tumors by in vivo molecular imaging and histological analysis of the tumor tissues. Following therapy, most of the remaining tumors were small, primary tumors that had low levels of HER2 expression and nanoparticle drug accumulation, thereby explaining their lack of therapeutic response. However, a few residual tumors had HER2-expressing tumor cells and detectable nanoparticle drug delivery but failed to respond, suggesting additional intrinsic resistant mechanisms. Nanoparticle retention in the small residual tumors, nevertheless, produced optical signals for detection by spectroscopic imaging. Conclusion: The inability to completely excise peritoneal metastatic tumors by debulking surgery as well as resistance to chemotherapy are the major clinical challenges for ovarian cancer treatment. This targeted cancer therapy has the potential for the development of effective treatment for metastatic ovarian cancer.

Dataset Information

Targeted delivery of platinum-taxane combination therapy in ovarian cancer.

Publications

Targeted delivery of platinum-taxane combination therapy in ovarian cancer.

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