title: Hyaluronan-decorated polymer nanoparticles targeting the CD44 receptor for the combined photo/chemo-therapy of cancer.
abstract: 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.
authors: Drug Delivery Laboratory, Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano 49, 80131, Napoli, Italy. quaglia@unina.it.
authors: Sara
authors: S
authors: Maiolino
authors: Francesca
authors: F
authors: Moret
authors: Claudia
authors: C
authors: Conte
authors: Aurore
authors: A
authors: Fraix
authors: Pasquale
authors: P
authors: Tirino
authors: Francesca
authors: F
authors: Ungaro
authors: Salvatore
authors: S
authors: Sortino
authors: Elena
authors: E
authors: Reddi
authors: Fabiana
authors: F
authors: Quaglia
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020099:Coated Materials, Biocompatible / Q000008:administration & dosage / Q000138:chemical synthesis; D003131:Combined Modality Therapy / Q000379:methods; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry / Q000493:pharmacokinetics*; D061986:MCF-7 Cells; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry / Q000648:ultrastructure; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000008:administration & dosage; D011108:Polymers / Q000737:chemistry; D011166:Porphyrins / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D020099:Coated Materials, Biocompatible; D018960:Hyaluronan Receptors; D053769:Nanocapsules; D017319:Photosensitizing Agents; D011108:Polymers; D011166:Porphyrins; C016136:tetraphenylporphine sulfonate; D004317:Doxorubicin; D006820:Hyaluronic Acid