Anti-tumor efficacy of hyaluronan-based nanoparticles for the co-delivery of drugs in lung cancer

Abstract

Combinations of therapeutic agents could synergistically enhance the response of lung cancer cells. Co-delivery systems capable of transporting chemotherapeutics with different physicochemical properties and with the simultaneous release of drugs remain elusive. Here, we assess the ability of nanoparticles of 30-nm diameter obtained from the self-assembly of hyaluronan-based copolymer targeting CD44 receptors to encapsulate both gefitinib and vorinostat for effective combinational lung cancer treatment. Drug loading was performed by nanoprecipitation. Drug release experiments showed a slow release of both drugs after 5 days. Using two- and three-dimensional lung adenocarcinoma cell cultures, we observed that the nanoparticles were mostly found at the periphery of the CD44-expressing spheroids. These drug-loaded nanoparticles were as cytotoxic as free drugs in the two- and three-dimensional systems and toxicity was due to apoptosis induction. In mouse models, intravenous injection of hyaluronan-based nanoparticles showed a selective delivery to subcutaneous CD44-overexpressing tumors, despite a significant liver capture. In addition, the systemic toxicity of the free drugs was reduced by their co-delivery using the nanoparticles. Finally, intrapulmonary administration of drug-loaded nanoparticles, to avoid a possible hepatic toxicity due to their accumulation in the liver, showed a stronger inhibition of orthotopic lung tumor growth compared to free drugs. In conclusion, hyaluronan-based nanoparticles provide active targeting partially mediated by CD44, less-toxic drug release and improved antitumor efficiency.

Multivalent and multifunctional polysaccharide-based particles for controlled receptor recognition

“…3c , the SPR signal of larger HA-particles (150 nm) was significantly higher than that of those of smaller diameters (30 nm). These observations are consistent with recent in vitro experiments performed on different lung cancer cell lines expressing different level of CD44 71 . Richter’s lab also recently observed the multivalent interaction between CD44 and high molecular weight HA by a multivalent interaction model 72 .…”

<p>^99mTc Radiolabeled HA/TPGS-Based Curcumin-Loaded Nanoparticle for Breast Cancer Synergistic Theranostics: Design, in vitro and in vivo Evaluation</p>

“…29,30 For instance, Jeannot et al reported HA-b-poly(γ-benzyl-L-glutamate) nanoparticles that could actively target to the CD44 receptor for delivery of vorinostat and gefitinib with strong tumor growth inhibition. 31 In another example, Gu et al synthesized HA-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate) that was capable of high drug loading and tumor-targeted delivery of bortezomib to myeloma in vivo. The HA-based nanoparticles exhibited a broad therapeutic window and enhanced tolerance with more effective growth suppression of CD44-overexpressed tumors.…”

Verteporfin-Loaded Lipid Nanoparticles Improve Ovarian Cancer Photodynamic Therapy In Vitro and In Vivo

“…The cellular uptake of NLC-verteporfin involved endocytosis processes, taking more time than free verteporfin, part of which can rapidly diffuse across cell membranes. NLC-verteporfin uptake was also shown in tumor spheroids, which mimic in vivo tumors with tumor cell interactions and gradients of nutrients and oxygen [22,23,24,25]. The slower kinetic of NLC-verteporfin uptake compared to free verteporfin did not impair the efficiency of verteporfin phototoxicity.…”

“…The mechanism by which the OVCAR3 cells resisted to PDT in 2D culture but not in spheroids is still unknown. These results highlighted that the toxicity of drugs significantly varied depending on whether it is assessed in spheroids or in monolayer cell cultures, and this thus underlined the importance of using spheroids before moving forward in vivo experiments in mice [22,23,25]. Further experiments are needed to study NLC-verteporfin uptake and cytotoxicity in multicellular spheroids, which will reproduce both tumor cells and microenvironment [24].…”