Multifunctional Nanotherapeutics for Cancer Treatment and Imaging

Summary

Principal Investigator: Tamara Minko
Abstract: Project Title: Multifunctional Nanotherapeutics for Cancer Treatment and Imaging The success of chemotherapeutic treatment of primary ovarian cancer, especially metastatic cells growing in ascitic fluid is limited by intrinsic and acquired resistance of cancer cells and adverse side effects of chemotherapy. Based on the results of our previous study and literature data, we hypothesized, that substantial enhancement in the effectiveness of treatment and imaging of drug resistant ovarian cancer and metastases can be achieved by the (1) induction of cancer cell death by at least two different anticancer drugs, (2) suppression of cancer cell resistance by siRNA targeted to proteins that play key roles in such resistance and (3) targeting drugs, imaging agents and siRNA specifically to ovarian cancer cells in primary tumor and metastases. Such an objective can only be achieved if several anticancer drugs are delivered to the ovarian tumor cells in combination with other active components that perform different specific functions for enhancing cellular uptake and efficiency of the main drugs specifically in cancer cells, limiting adverse side effects, and preventing the development and/or suppression of the existing drug resistance. In the proposed study, we plan to apply nanotechnology approaches to the development and evaluation of such multicomponent multifunctional nanotherapeutics. The long-term objective of the proposed research is to verify the hypothesis and develop a mixture (cocktail) of novel multifunctional Nanotechnology-based Drug Delivery Systems (NDDS) that will significantly increase the efficacy of the chemotherapy of primary ovarian cancer and intraperitoneal metastases while minimizing side effects on healthy organs. A hydroxyl terminated PAMAM-OH and internally quaternized and surface-acetylated Poly(amido amine) dendrimer (QPAMAM-NHAc) will be used as a nanocarrier to deliver anticancer drugs and siRNA, respectively. In addition, each NDDS will contain a tumor-specific targeting moiety (peptide) and one active component (anticancer drug or siRNA or fluorescent dye). Paclitaxel and cisplatin/carboplatin will be evaluated as anticancer drugs - cell death inducers. siRNA targeted to MDR1 and CD44 mRNA will be investigated as suppressors of pump resistance. siRNA targeted to BCL2 mRNA will be studied as a suppressor of nonpump resistance. Luteinizing Hormone-Releasing Hormone (LHRH) peptide will be used as ovarian cancer-specific targeting moiety. Established human multidrug resistant ovarian cancer cell lines as well as cells isolated from primary tumor and malignant ascites from patients with advanced multidrug resistant ovarian carcinoma will be used to create ectopic subcutaneous and orthotopic intraperitoneal models in nude mice. Intravenous systemic and intraperitoneal local administrations of NDDS will be compared. The results of the proposed research will be used to design novel multifunctional nanotechnology approaches for the treatment of different cancers.
Funding Period: 2010-07-01 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Multifunctional tumor-targeted polymer-peptide-drug delivery system for treatment of primary and metastatic cancers
    Pooja Chandna
    Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey 08854 8020, USA
    Pharm Res 27:2296-306. 2010
  2. ncbi Multifunctional nanomedicine platform for cancer specific delivery of siRNA by superparamagnetic iron oxide nanoparticles-dendrimer complexes
    Oleh Taratula
    Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
    Curr Drug Deliv 8:59-69. 2011
  3. pmc Multifunctional triblock Nanocarrier (PAMAM-PEG-PLL) for the efficient intracellular siRNA delivery and gene silencing
    Mahesh L Patil
    Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States
    ACS Nano 5:1877-87. 2011
  4. ncbi Innovative strategy for treatment of lung cancer: targeted nanotechnology-based inhalation co-delivery of anticancer drugs and siRNA
    Oleh Taratula
    Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 8020, USA
    J Drug Target 19:900-14. 2011
  5. ncbi Two-in-one: combined targeted chemo and gene therapy for tumor suppression and prevention of metastases
    Min Zhang
    Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
    Nanomedicine (Lond) 7:185-97. 2012
  6. pmc Genotoxicity of different nanocarriers: possible modifications for the delivery of nucleic acids
    Vatsal Shah
    Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854 8020, USA
    Curr Drug Discov Technol 10:8-15. 2013
  7. pmc Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA
    Oleh Taratula
    Department of Pharmaceutics, Ernest Mario School of Pharmacy, Piscataway 08854, USA Department of Pharmaceutical Sciences, Oregon State University, Corvallis 97331, USA
    J Control Release 171:349-57. 2013
  8. pmc Nanotechnology approaches for inhalation treatment of fibrosis
    Ronak Savla
    Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
    J Drug Target 21:914-25. 2013
  9. pmc Targeted nanomedicine for suppression of CD44 and simultaneous cell death induction in ovarian cancer: an optimal delivery of siRNA and anticancer drug
    Vatsal Shah
    Authors Affiliations Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway Rutgers Cancer Institute of New Jersey and Department of Obstetrics and Gynecology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey and Department of Pharmaceutical Sciences, Oregon State University, Corvallis, Oregon
    Clin Cancer Res 19:6193-204. 2013

Detail Information

Publications9

  1. ncbi Multifunctional tumor-targeted polymer-peptide-drug delivery system for treatment of primary and metastatic cancers
    Pooja Chandna
    Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey 08854 8020, USA
    Pharm Res 27:2296-306. 2010
    ..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...
  2. ncbi Multifunctional nanomedicine platform for cancer specific delivery of siRNA by superparamagnetic iron oxide nanoparticles-dendrimer complexes
    Oleh Taratula
    Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
    Curr Drug Deliv 8:59-69. 2011
    ....
  3. pmc Multifunctional triblock Nanocarrier (PAMAM-PEG-PLL) for the efficient intracellular siRNA delivery and gene silencing
    Mahesh L Patil
    Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States
    ACS Nano 5:1877-87. 2011
    ..In addition, triblock nanocarrier/siRNA polyplexes showed excellent stability in human plasma...
  4. ncbi Innovative strategy for treatment of lung cancer: targeted nanotechnology-based inhalation co-delivery of anticancer drugs and siRNA
    Oleh Taratula
    Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 8020, USA
    J Drug Target 19:900-14. 2011
    ..Therefore, the proposed cancer-targeted MSN-based system for complex delivery of drugs and siRNA has high potential in the effective treatment of lung cancer...
  5. ncbi Two-in-one: combined targeted chemo and gene therapy for tumor suppression and prevention of metastases
    Min Zhang
    Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
    Nanomedicine (Lond) 7:185-97. 2012
    ..To develop an approach for the effective treatment of ovarian tumor, prevention of metastases and limitation of side effects...
  6. pmc Genotoxicity of different nanocarriers: possible modifications for the delivery of nucleic acids
    Vatsal Shah
    Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854 8020, USA
    Curr Drug Discov Technol 10:8-15. 2013
    ..We proposed modifications of both types of dendrimers and SPIO nanoparticles that substantially decreased their genotoxicity and allowed for an efficient intracellular delivery of nucleic acids...
  7. pmc Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA
    Oleh Taratula
    Department of Pharmaceutics, Ernest Mario School of Pharmacy, Piscataway 08854, USA Department of Pharmaceutical Sciences, Oregon State University, Corvallis 97331, USA
    J Control Release 171:349-57. 2013
    ....
  8. pmc Nanotechnology approaches for inhalation treatment of fibrosis
    Ronak Savla
    Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
    J Drug Target 21:914-25. 2013
    ..This review is focused on different approaches to the treatment of respiratory manifestations of CF as well as on methods of pulmonary delivery of therapeutics...
  9. pmc Targeted nanomedicine for suppression of CD44 and simultaneous cell death induction in ovarian cancer: an optimal delivery of siRNA and anticancer drug
    Vatsal Shah
    Authors Affiliations Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway Rutgers Cancer Institute of New Jersey and Department of Obstetrics and Gynecology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey and Department of Pharmaceutical Sciences, Oregon State University, Corvallis, Oregon
    Clin Cancer Res 19:6193-204. 2013
    ..We hypothesize that a developed cancer-targeted delivery system that combines CD44 siRNA with paclitaxel would successfully deliver its payload inside cancer cells, effectively induce cell death, and prevent metastases...

Research Grants30