NANOTHER – TAMs-targeted and externally controlled nanotheranostics of triple-negative-breast-cancer

Summary

Triple-negative breast cancer (TNBC) represents 20% of the 3 million breast cancers diagnosed in women worldwide every year. In Portugal, the incidence of breast cancer is 118.5 women per 100000 population, which represents 30% of the newly diagnosed cancer cases in women every year and continues to show a high mortality rate.

The only systemic therapy currently available for patients with TNBC is (neo)adjuvant therapy with various cytotoxic chemotherapeutic agents. However, the lack of targeted therapeutic options, together with the limited efficacy of current treatments as well as the adverse effects associated with them, demands an urgent effort to develop novel targeted therapies and early diagnostic methods. Triple-negative breast cancer (TNBC) is often among the highest-grade and poorer prognosis breast cancers, mainly because targeted therapy is not available. Therefore, there is an urgent demand to discover specific targets and develop novel targeted therapies as well as early diagnostic methods.

The main objective of this project was to ameliorate the prognosis of TNBC through the preparation and preclinical validation (in vitro plus in vivo) of a targeted theranostic nanoparticle/probe that is able to specifically recognize tumor-associated macrophages (TAMs), offering a non- invasive imaging capability by MRI together with a synergic magnetic hyperthermia (MH)and chemotherapy treatment against TNBC. This initiative represents an innovative and ground-breaking use of tailored hybrid nanocomposites as an innovative and tangible solution in the field of targeted drug delivery against cancer, TNBC in particular. The lack of targeted therapeutic options against TNBC, the limited efficacy of current treatments and the well-known secondary effects of conventional chemotherapeutic treatments open the gate to develop novel targeted therapies as well as early diagnostic methods. Imaging and externally controlled drug delivery capabilities, in combination with magnetic hyperthermia and active targeting, will be integrated into one single platform.

The expected scientific advances will contribute to the ultimate clinical translation and a wide-range of innovations with potential to impact the triple-negative breast cancer therapy, being also a step forward on the way to targeted, image-guided therapies of cancer. To the best of the team’s knowledge, there is no one single theranostic nanomedicine that made it into the clinics. Also, the clinical translation of developed controlled drug delivery systems is very limited and just a few examples can be found in the market, which is fully dominated by the small molecule drugs. Thus, the combination of a not yet existing market of ‘theranostic medicines’ (estimated in 20 bn) and that of controlled drug delivery (70bn) constitutes a new medical framework and market opportunity for specific theranostic systems with proved targeted, imaging and therapeutic efficiencies.

 

Title TAMs – Targeted and externally controlled nanotheranostics of triple-negative-breast-cancer
Reference UUTAP-EXPL/NTec/0038/2017
Scientific Area Nanotechnologies
Funding € 98 550,00 plus matched funding at UT Austin
Leading Institution Laboratório Ibérico Internacional de Nanotecnologias (INL)
Participating Institutions The University of Austin at Texas (UT Austin)
Universidade do Minho (UM)
Duration 26 months
Begin date November 1, 2018
End date December 31, 2020
Keywords Triple-negative-breast Cancer, Nanotheranostics, Magnetic Resonance Imaging, Hyperthermia-induced Drug Delivery

Main Highlights

  • Synthesis of biocompatible water-dispersable theranostic DOX-loaded magnetic wax formulations with magnetic and pH-responsiveness, offering contrast enhancement by MRI and combinatorial thermochemotherapy outcomes;
  • Functional performance validation: T2-MRI contrast enhancement, high magnetic hyperthermia efficiency and controlled DOX release;
  • Active targeting to M2-type tumor-associated macrophages at the acidic pH found in the tumoral microenvironment;
  • In vivo results show a preferential accumulation of the nanoformulations in the tumor tissue. Also, antitumor efficacy studies revealed an efficient reduction of the tumor volume (comparable to that of free drug administration) but with a complete reduction of systemic toxicity;
  • Furthermore, control (non-functionalized) formulations were demonstrated to be suitable MRI contrast agents in vivo when administered systemically, as per the relaxation time shortening observed in the tumor area, rendering these magnetic formulations excellent theranostic agents for cancer management.

Indicators

  • 9 Published papers in peer-reviewed Journals and Conferences. 1 Jointly authored (PT-US);
  • 5 Doctoral students and 1 MSc. student involved in research work;
  • 1 Prototype (Available water-dispersion of pH-responsive magnetic nanocomposites showing theranostic properties);
  • 2 Scientific events organized;
  • 1 Award:

Feature cover award – Carolina L. de Moura, Juan Gallo, Lorena García-Hevia, Otilia D. L. Pessoa, Nagila M. P. S. Ricardo and Manuel Bañobre-López. Magnetic Hybrid Wax Nanocomposites as Externally Controlled Theranostic Vehicles: High MRI Enhancement and Synergistic Magnetically Assisted Thermo/Chemo Therapy Chem. Eur. J. 2020, 26, 4531 – 4538. COVER FEATURE 20/2020. – PT team – International publication.

Papers and Communications

  • Julia Jiménez-López, Lorena García-Hevia, Consolación Melguizo, Jose Carlos Prados, Manuel Bañobre-López and Juan Gallo. Evaluation of novel magnetic wax nanocomposite vehicles as cancer combinatorial therapy agents. Pharmaceutics (in press)
  • Yong Sze Ong, Manuel Bañobre-López, Sofia Costa Lima, Salette Reis. A multifunctional nanomedicine platform for co-delivery of methotrexate and mild hyperthermia towards breast cancer therapy. Materials Science & Engineering C (in press)
  • Cátia Rocha, Milene Silva, Manuel Bañobre-López and Juan Gallo. (Para)Magnetic hybrid nanocomposites for dual MRI detection and treatment of solid tumours. Chem. Comm. (in press)
  • Carolina L. de Moura, Juan Gallo, Lorena García-Hevia, Otilia D. L. Pessoa, Nagila M. P. S. Ricardo and Manuel Bañobre-López. Magnetic Hybrid Wax Nanocomposites as Externally Controlled Theranostic Vehicles: High MRI Enhancement and Synergistic Magnetically Assisted Thermo/Chemo Therapy. Chem. Eur. J. 2020, 26, 4531 – 4538. COVER FEATURE 20/2020
  • J Wang, Y Peng, H Xu, Z Cui, RO Williams III. The COVID-19 vaccine race: challenges and opportunities in vaccine formulation. APPS PharmSciTech. (in press)
  • Lorena García-Hevia, Manuel Bañobre-López and Juan Gallo. Recent progress on manganese-based nanostructures as responsive MRI contrast agents. Chem Eur J 2019, 7;25 (2), 431-441
  • Lorena G. Hevia, Stefania Scialla, Jieliang Wang, Efres Belmonte, I. Casafont, M. L. Fanarraga, Juan Gallo, Zhengrong Cui and Manuel Bañobre- López. Magnetic Hybrid Nanocomposites as theranostic platform for cancer theranostics. Conference: Nanomed Europe 2019. Place and date: Braga, June 17th, 2019
  • J Wang, MS Hanafy, J Leal, H Xu, D Ghosh, RO Williams III, HDC Smyth, Z Cui*, Aerosol performance of thin-film freeze-dried and spray-dried TNF-alpha siRNA-solid lipid nanoparticles for potential pulmonary delivery. 16th Annual Louis C. Littlefield Celebrating Pharmacy Research Excellence Day in Professional, Graduate, and Postgraduate Programs. April 15, 2020, Virtual in Austin, Texas (Abstract # 56)
  • J Wang, AM Aldayel, HL O’Mary, H Xu, Z Cui*, The aerosol performance of TNF-a siRNA solid lipid nanoparticles for potential pulmonary delivery. AAPS PharmSci 360. San Antonio, TX, Nov 3-6, 2019

Project Team

Manuel Bañobre

Principal Investigator in Portugal
NANOTHER

Zhengrong Cui

Principal Investigator in Austin
NANOTHER