Functionalizable oxanorbornane-based head-group in the design of new Non-ionic amphiphiles and their drug delivery properties.

Abstract

A new group of non-ionic amphiphiles with short alkyl chains and functionalizable oxanorbornane-based head group for drug delivery application are presented. They can be prepared through a sequence that starts with cycloaddition of Boc-protected furfuryl amine with maleic anhydride and reduction of the resulting adduct with LiAlH4 to get a diol intermediate. Introduction of alkyl chains through these primary hydroxyl groups and subsequent head-group modification via cis-hydroxylation resulted in a number of new amphiphiles in good yields. They were characterized by various spectro-analytical techniques and then subjected to drug-delivery studies using ibuprofen as a model drug. Functionalization of the head group through the amine functionality was also done with an intention to improve lipid packing to get better drug-loading and release properties. Irrespective of the nature of groups attached through this amine unit, all amphiphiles with short alkyl chains were found to assemble into spherical aggregates when drop-casted from various organic solvents. The same assembly preference prevailed in their formulations containing lipid-cholesterol-drug in 1: 0.5:1 ratio as well, and these particles had diameters <300nm. Apart from good drug-loading efficiencies, these amphiphiles exhibited controlled release properties and did not show any indication of toxicity when assayed against NIH3T3 cells. The formulation based on lipid having a phenylalanine unit on the head group (1.10c) turned out to be the best in this series which showed a loading efficiency of 57.6% with a controlled release of ~42% by end of 24h. Because of efficient layering that is facilitated by hydrogen bonding involving well-directed hydroxyl groups on the head group, amphiphiles with alkyl chains as short as C5 are able to act as efficient drug delivery systems, which is one of the highlights of this work.