title: Design of multifunctional non-viral gene vectors to overcome physiological barriers: dilemmas and strategies.
abstract: Gene-based therapeutics hold great promise for medical advancement and have been used to treat various human diseases with mixed success. However, their therapeutic application in vivo is limited due largely to several physiological barriers. The design of non-viral gene vectors with the ability to overcome delivery obstacles is currently under extensive investigation. These efforts have placed an emphasis on the development of multifunctional vectors able to execute multiple tasks to simultaneously overcome both extracellular and intracellular obstacles. However, the assembly of these different functionalities into a single system to create multifunctional gene vectors faces many conflicts that largely limit the safe and efficient application of lipoplexes and polyplexes in a systemic delivery. In the review, we have described the dilemmas inherent in the design of a viable, non-viral gene vector equipped with multiple functionalities. The strategies directed towards individual delivery barriers are first summarized, followed by a focus on the design of so-called smart multifunctional vectors with the capability to overcome the delivery difficulties of gene medicines, including the so-called the "polycation dilemma", the "PEG dilemma" and the "package and release dilemma".
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, 312 Mugar Life Sciences Building, 360 Huntington Avenue, Northeastern University, Boston, MA 02115, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Jaydev R
authors.initials: JR
authors.lastname: Upponi
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Torchilin
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D001776:Blood Circulation Time / Q000379:methods; D002467:Cell Nucleus / Q000378:metabolism*; D004337:Drug Carriers / Q000008:administration & dosage; D011992:Endosomes / Q000378:metabolism; D018390:Gene Targeting / Q000379:methods; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000628:therapy; D011073:Polyamines / Q000378:metabolism; D000071228:Polyelectrolytes; D011092:Polyethylene Glycols / Q000008:administration & dosage
chemical_list: D004337:Drug Carriers; D011073:Polyamines; D000071228:Polyelectrolytes; D011092:Polyethylene Glycols