title: Self-assembled nanoparticles from hyaluronic acid-paclitaxel prodrugs for direct cytosolic delivery and enhanced antitumor activity.
abstract: A prodrug-based nanosystem obtained by formulating prodrug and nanotechnology into a system is one of the most promising strategies to enhance drug delivery for disease treatment. Herein, we report a new nanosystem based on HA-PTX conjugates (HA-PTX Ns), which penetrated across cell membranes into cytosol, thus enhancing paclitaxel (PTX) delivery. HA-PTX Ns were successfully obtained based on HA-PTX, and their average particle size was approximately 200 nm. Importantly, unlike other prodrug-based nanosystems, HA-PTX Ns obtained cellular entry without entrapment within the lysosomal-endosomal system by using pathways including clathrin-mediated endocytosis, microtubule-associated internalization, macropinocytosis and cholesterol-dependence. Due to significant accumulation in tumors, HA-PTX Ns had more than a 4-fold decrease in tumor volume on day 14 in contrast with PTX alone. In conclusion, HA-PTX Ns could enter cells, bypass the lysosomal-endosomal system and improve PTX delivery.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Chaoran
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: weihe@cpu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yaqi
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Qin
authors.affiliation: National Engineering and Research Center for Target Drugs, Lianyungang 222047, PR China.
authors.forename: Lingjia
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: lifangyin@hotmail.com.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yin
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism*; D004337:Drug Carriers; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage*; D011092:Polyethylene Glycols; D011355:Prodrugs / Q000008:administration & dosage*; D051381:Rats
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008823:Micelles; D011355:Prodrugs; D011092:Polyethylene Glycols; D006820:Hyaluronic Acid; D017239:Paclitaxel
keywords: Adipic acid dihydrazide (PubChem CID: 66117); Antitumor activity; Carbodiimide hydrochloride (PubChem CID: 15908); Cytosolic delivery; Diphenylphosphinic chloride (PubChem CID: 73910); Fluorescein isothiocyanate (PubChem CID: 18730); IR783 (PubChem CID: 46873808); Internalization pathway; MTT (PubChem CID: 16218671); Nanoparticles; Paclitaxel; Paclitaxel (PubChem CID: 44155032); Prodrug; Pyridine (PubChem CID: 1049); Self-assembly; Succinic anhydride (PubChem CID: 7922); Triethylamine (PubChem CID: 8471)