Hyaluronan-decorated polymer nanoparticles targeting the CD44 receptor for the combined photo/chemo-therapy of cancer

• Published in: Nanoscale Vol. 7; no. 13; pp. 5643 - 5653
• Main Authors: Maiolino, Sara, Moret, Francesca, Conte, Claudia, Fraix, Aurore, Tirino, Pasquale, Ungaro, Francesca, Sortino, Salvatore, Reddi, Elena, Quaglia, Fabiana
• Format: Journal Article
• Language: English
• Published: England 01.01.2015
• Subjects: Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - chemistry; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer; Cell Line, Tumor; Cell Survival - drug effects; Coated Materials, Biocompatible - administration & dosage; Coated Materials, Biocompatible - chemical synthesis; Combined Modality Therapy - methods; Diffusion; Doxorubicin - administration & dosage; Drugs; Humans; Hyaluronan Receptors - metabolism; Hyaluronic Acid - chemistry; Hyaluronic Acid - pharmacokinetics; MCF-7 Cells; Media; Nanocapsules - administration & dosage; Nanocapsules - chemistry; Nanocapsules - ultrastructure; Nanoparticles; Nanostructure; Photochemotherapy - methods; Photosensitizing Agents - administration & dosage; Polymers - chemistry; Porphyrins; Porphyrins - administration & dosage; Receptors; Shells; Treatment Outcome
• ISSN: 2040-3364; 2040-3372
• DOI: 10.1039/c4nr06910b

In the attempt to develop novel concepts in designing targeted nanoparticles for combination therapy of cancer, we propose here CD44-targeted hyaluronan-decorated double-coated nanoparticles (dcNPs) delivering the lipophilic chemotherapeutic docetaxel (DTX) and an anionic porphyrin (TPPS₄). dcNPs are based on electrostatic interactions between a negative DTX-loaded nanoscaffold of poly(lactide-co-glycolide), a polycationic shell of polyethyleneimine entangling negatively-charged TPPS₄ and finally decorated with hyaluronan (HA) to promote internalization through CD44 receptor-mediated endocytosis. DTX/TPPS₄-dcNPs, prepared through layer-by-layer deposition, showed a hydrodynamic diameter of around 180 nm, negative zeta potential and efficient loading of both DTX and TPPS₄. DTX/TPPS₄-dcNPs were freeze-dried with trehalose giving a powder that could be easily dispersed in different media. Excellent stability of dcNPs in specific salt- and protein-containing media was found. Spectroscopic behavior of DTX/TPPS₄-dcNPs demonstrated a face-to-face arrangement of the TPPS₄ units in non-photoresponsive H-type aggregates accounting for an extensive aggregation of the porphyrin embedded in the shell. Experiments in MDA-MB-231 cells overexpressing the CD44 receptor demonstrated a 9.4-fold increase in the intracellular level of TPPS₄ delivered from dcNPs as compared to free TPPS₄. Light-induced death increased tremendously in cells that had been treated with a combination of TPPS₄ and DTX delivered through dcNPs as compared with free drugs, presumably due to efficient uptake and co-localization inside the cells. In perspective, the strategy proposed here to target synergistic drug combinations through HA-decorated nanoparticles seems very attractive to improve the specificity and efficacy of cancer treatment.