title: Polyphosphoester nanoparticles as biodegradable platform for delivery of multiple drugs and siRNA.
abstract: Delivery of multiple therapeutics and/or diagnostic agents to diseased tissues is challenging and necessitates the development of multifunctional platforms. Among the various strategies for design of multifunctional nanocarriers, biodegradable polyphosphoester (PPE) polymers have been recently synthesized via a rapid and simple synthetic strategy. In addition, the chemical structure of the polymer could be tuned to form nanoparticles with varying surface chemistries and charges, which have shown exceptional safety and biocompatibility as compared to several commercial agents. The purpose of this study was to exploit a mixture of PPE nanoparticles of cationic and neutral surface charges for multiple delivery of anticancer drugs (ie, sorafenib and paclitaxel) and nucleic acids (ie, siRNA). Cationic PPE polymers could efficiently complex siRNA, and the stability of the nanoparticles could be maintained in physiological solutions and upon freeze-drying and were able to deliver siRNA in vivo when injected intravenously in mice. Commercially available cationic polyethylenimine polymer had LD50of ca. 61.7 mg/kg in mice, whereas no animal died after injection of the cationic PPE polymer at a dose of >130 mg/kg. Neutral PPE nanoparticles were able to encapsulate two hydrophobic drugs, namely, sorafenib and paclitaxel, which are commonly used for the treatment of hepatocellular carcinoma. Mixing the neutral and cationic PPE nanoparticles did not result in any precipitation, and the size characteristics of both types of nanoparticles were maintained. Hence, PPE polymers might have potential for the delivery of multiple drugs and diagnostic agents to diseased tissues via simple synthesis of the individual polymers and assembly into nanoparticles that can host several drugs while being mixed in the same administration set, which is of importance for industrial and clinical development.
authors.affiliation: Assiut International Center of Nanomedicine, Al-Rajhy Liver Hospital, Assiut University, Assiut, Egypt.
authors.forename: Hadeel
authors.initials: H
authors.lastname: Elzeny
authors.affiliation: Departments of Chemistry, Chemical Engineering and Materials Science and Engineering, Texas A&M University, College Station, TX, USA.
authors.forename: Fuwu
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Assiut International Center of Nanomedicine, Al-Rajhy Liver Hospital, Assiut University, Assiut, Egypt.
authors.forename: Esraa N
authors.initials: EN
authors.lastname: Ali
authors.affiliation: Assiut International Center of Nanomedicine, Al-Rajhy Liver Hospital, Assiut University, Assiut, Egypt.
authors.forename: Heba A
authors.initials: HA
authors.lastname: Fathi
authors.affiliation: School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
authors.forename: Shiyi
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Departments of Chemistry, Chemical Engineering and Materials Science and Engineering, Texas A&M University, College Station, TX, USA.
authors.forename: Richen
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Faculty of Medicine.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: El-Mokhtar
authors.affiliation: Department of Surgery, Faculty of Medicine, Assiut University, Assiut, Egypt.
authors.forename: Mostafa A
authors.initials: MA
authors.lastname: Hamad
authors.affiliation: Departments of Chemistry, Chemical Engineering and Materials Science and Engineering, Texas A&M University, College Station, TX, USA; Laboratory for Synthetic-Biologic Interactions, Department of Chemistry, Texas A&M University, College Station, TX, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Wooley
authors.affiliation: Assiut International Center of Nanomedicine, Al-Rajhy Liver Hospital, Assiut University, Assiut, Egypt; Laboratory for Synthetic-Biologic Interactions, Department of Chemistry, Texas A&M University, College Station, TX, USA; Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut; Misr University for Science and Technology, 6th of October City, Egypt.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Elsabahy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D015394:Molecular Structure; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077157:Sorafenib; D013329:Structure-Activity Relationship; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D010671:Phenylurea Compounds; D011108:Polymers; D034741:RNA, Small Interfering; D009536:Niacinamide; D000077157:Sorafenib; D017239:Paclitaxel
keywords: biodegradable nanoparticles; chitosan; paclitaxel; polyethylenimine; polyphosphoester; siRNA; sorafenib