The treatment of lung cancer requires new therapeutic approaches beyond chemotherapy and radiotherapy. The delivery of anticancer drugs with biopolymer-based nanoparticles targeting tumors is a promising approach.
Non-small cell lung cancer is a very common type of cancer that is currently treated by chemotherapy or radiotherapy with known side effects. Molecularly targeted treatments are now coming to the fore, and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been proposed. However, only a minority of patients with lung cancer responds to therapy, alone or in combination and there is still a need to develop new approaches such as those offered by drug delivery systems (DDS). The central concept of DDS is to protect the drug molecule against its degradation, to reduce its apparent toxicity <br />and to control its release in time and space. Herein, the goal is to design nanoparticles from biopolymers to encapsulate a combination of tyrosine kinase inhibitors for lung cancer treatment. It is believed that same particles could be successfully used for other types of cancers. <br />
An amphiphilic copolymer with self-assembly properties will be used to form nanoparticles and encapsulate drugs. The biodistribution and the therapeutic efficacy of the particles will be evaluated on mice using non-invasive imaging techniques.
The project aims at carrying out fundamental research on new drug delivery systems for lung cancer treatment. It is believed that the use of polysaccharides to elaborate nanoparticles can be of high interest for both targeting properties and biological properties such as biocompatibility. It is also expected that the project will provide new data on the encapsulation of tyrosine kinase inhibitors and their in vivo biodistribution. Besides, the use of different combinations of anticancer drugs could be patented.
Main results obtained during the first six months of the project are the optimized synthesis of polymer bricks for nanoparticle formation and the molecular targeting in mice bearing different types of lung cancer.
The translation to human clinical trials could be possible depending on the results obtained on mice and rats. It is also expected that the use of nanoparticles will reduce the amount of injected drug and thus decrease the significance of side effects. This could be beneficial for other types of cancer as well.
B. Busser, L. Sancey, V. Josserand, C. Niang, M. C. Favrot, J. L. Coll, A. Hurbin, MolTher. 2010, 18, 528.
B. Busser, L. Sancey, V. Josserand, C. Niang, S. Khochbin, M. C. Favrot, J. L.Coll, A. Hurbin, Mol Ther. 2010, 18, 536.
Because the lung cancer is one of the most fatal diseases, there is an urgent need to propose new therapeutic approaches in addition to current radiotherapy and chemotherapy. In this call, we want to evaluate the therapeutic efficacy of new polysaccharide-block-polypeptide copolymer nanosized vesicles (polymersomes) loaded with specific Active Pharmaceutical Ingredient. The biodegradability and the non-toxicity of the copolymer, the stability of vesicles in physiological medium, the possibility of co-encapsulating drugs of different polarities and a marked antitumor activity in rat breast cancer model are some of the hallmarks of the proposed polymeric system. Most of the research has been performed so far with copolymers containing a hyaluronan block, which is known for its relative affinity towards CD 44 receptors up-regulated on some cancer cells and promising preliminary tumour regression effects have been obtained To go further in the development of polysaccharide based polymersomes and to fully ascertain their biological potential for lung cancer treatment, we propose in this call to study the role of various molecular and colloidal parameters on polymersome biodistribution and tumor regression. At first and in addition to hyaluronan, we wish to evaluate low molecular weight heparin as polysaccharide block. This polymer is known to be stealth in blood circulation and to have also some anticancer properties. Then, we wish to study precisely the influence of the polymersome size (below and above 100 nm) on the biodistribution, using the so-called nanoprecipitation method to form vesicles. Polymersomes will be endowed with active targeting capabilities by grafting at their surface a newly discovered ligand, the iRGD peptide, which has been shown to promote the penetration of co-administered drugs deep into tumor tissues. The dissociation of the polymersomes with subsequent drug release in the tumor microenvironment might considerably improve the therapeutics effects of the drugs. This will be achieved by introducing in the copolymer chain a specific peptide (PVGLIG), which is cleavable by metalloproteinases MMP-2 and MMP-9, two important tumor-associated enzymes. Two drug formulations have been chosen for evaluating polymersomes against lung cancer. EGFR inhibitors (gefitinib, erlotinib) are currently used for non-small cell lung cancer treatment, but numerous resistance mechanisms have been described. Combination of targeted therapies could overcome lung cancer resistance to these treatments. Erlotinib has been chosen as model chemotherapeutic agent to be encapsulated, or co-encapsulated with histone deacetylase inhibitor (vorinostat) chosen for its ability to inhibit the mechanisms of resistance to anti-EGFR treatments. We will also encapsulate Liminib, a new compound with promising anti-cancer and anti-metastatic properties that can overcome the problems of drug resistance. Cell lines with various levels of treatment resistance and of CD44 and integrins expression have been selected. The effect of drug-loaded polymersomes in vitro and in vivo on lung tumors regression in nude mice will be analyzed. Anti-metastatic efficacy of Liminib will be also studied using in vivo model of metastasis invasion. Lung tumor progression, metastasis development and nanoparticules therapeutic efficacy will be followed using non-invasive optical imaging (Optimal platform). The complementary of partners, the first with a strong expertise in chemistry and formulation of colloidal systems for drug delivery, and the second being specialized in the study of molecular mechanisms of resistance to treatment of lung tumor cells and non-invasive optical imaging, is expected to quickly obtain relevant results on the biodistribution and the therapeutic effect of polymersomes. In terms of scientific and technologic exploitation, we aim to gather sufficient biological data in view of considering the possibility of preclinical development as next step.
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION AQUITAINE LIMOUSIN (Divers public)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION AQUITAINE LIMOUSIN
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION DE LYON
Help of the ANR 412,152 euros
Beginning and duration of the scientific project: January 2012 - 36 Months