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The in vivo efficacy of doxorubicin (DOX)-loaded poly(γ-benzyl l-glutamate)- block -hyaluronan (PBLG 23 - b -HYA 10 )-based polymersomes (PolyDOX) was evaluated. Samples were efficiently labeled with technetium-99m radionuclide with good stability for in vivo studies. PolyDOX enhanced circulation time compared to free DOX. Biodistribution studies revealed selective accumulation of PolyDOX in the Ehrlich ascites tumor (EAT) as a result of passive accumulation and active targeting (CD44-mediated endocytosis) in EAT-bearing mice. Toxicity studies demonstrated PolyDOX is a safe drug carrier, and no hemolysis was observed with PolyDOX equivalent to 200 μg/mL of free DOX. PolyDOX dominantly controlled tumor growth by delaying doubling time of EATs compared to free DOX over 30 days after treatment. PolyDOX also increased life span six times more than free DOX. Hence, it is reasonable to expect that higher DOX levels attributable to PolyDOX improve the therapeutic index and reduce side effects due to site-specific drug accumulation. From the Clinical Editor In this preclinical project, doxorubicin loaded polymersomes enhanced intracellular uptake of doxorubicin in a murine model of Ehrlich Ascites Tumor (EAT) through CD44 receptor mediated endocytosis, resulting in prolonged Tumor Doubling Time and increase in life span of mice.

International audience; We have investigated the intracellular delivery of doxorubicin (DOX) loaded poly(gamma-benzyl L-glutamate)block-hyaluronan (PBLG-b-HYA) based polymersomes (PolyDOX) in high (MCF-7) and low (U87) CD44 expressing cancer cell models. DOX was successfully loaded into polymersomes using nanoprecipitation method and in vitro drug release pattern were achieved at pH 5.5 and 7.4 up to 10 days. Block copolymer vesicles without loaded DOX were non cytotoxic in both cells at concentration 150-650 mu g/mL. Flow cytometry data suggested successful uptake of PolyDOX in cells and high accumulation was found in MCF-7 than U87 cells. Microscopy imagings revealed that in MCF-7 cells PolyDOX was more in cytoplasm and free DOX in nuclei, whereas in U87 cells free DOX was also found in the cytoplasm. Cytotoxicity of the drug was concentration and exposure time dependent. In addition, PolyDOX significantly enhanced reactive oxygen species (ROS) level in both cells. PolyDOX also suppressed growth of breast tumor on female Sprague-Dawley (SD) rats as compared to phosphate buffer saline pH 7.4 (PBS) control group. In addition reduced level of serum enzymes (LDH and CPK) by PolyDOX formulation indicated less cardiotoxicity of DOX after loading in polymersomes. Results suggest that intracellular delivery of PolyDOX was depended on the CD44 expression level in cells due to, presence of hyaluronic acid on the surface of polymersomes, and could be used as a self-targeting drug delivery cargo in over-expressed CD44 glycoprotein cells of breast cancer.

International audience; Using "click chemistry" as an easy and versatile synthetic strategy to combine hyaluronan and polyglutamate blocks, we have prepared nanovesicles (polymersomes) that present a controlled size, excellent colloidal stability, and a high loading capacity for hydrophilic and hydrophobic drugs. The unique feature of our concept is the use of hyaluronan, a polysaccharide with known capacity for targeting cancer-related protein receptors, as the hydrophilic portion of a block copolymer system. The cytotoxicity and internalization mechanism of doxorubicin-loaded polymersomes have been evaluated in C6 glioma tumor cell lines. The dual purpose served by hyaluronan, as both a hydrophilic block critical to vesicle formation and as a binding agent for biological targets, breaks new ground in terms of multifunctional nanomaterial design for drug delivery.

International audience; Drug, gene and protein delivery is a very challenging and exciting area in nanobiotechnology where block copolymers are increasingly considered especially as carriers for chemotherapeutic agents in treatment of various cancers. Cancer chemotherapy is particularly challenging because of nonselective distribution of drugs, associated severe toxicity, multidrug resistance and chronic treatments influencing the quality-adjusted life of patients. These limitations lead to incomplete cure and render many drugs ineffective in treating cancers. Liposomes are currently more advanced in clinical trials and industrial developments but they lack stability and pose difficulties in functionalizing it. More recently, various types of polymer-based nano-constructs have been designed, synthesized and used for the cancer chemotherapy applications. This review discusses the most significant and recent literature developments on specific self-assembled block copolymers as a carrier system such as micelles and vesicles, which can be successfully used to enhance the solubility of hydrophobic drugs, helpful in targeting selective sites in the body, delivering active molecules in a control manner and reducing the side effects, and their role in treatment of cancer.