The advent of nanotechnology is revolutionizing drug delivery in terms of improving drug efficacy and safety. Both polymer-based and lipid-based drug-loaded nanocarriers have demonstrated clinical benefit. However, to further address the multifaceted drug delivery challenges and further expand the spectrum of therapeutic applications, hybrid lipid-polymer nanocomposites have been designed to merge the beneficial features of both polymeric drug delivery systems and liposomes in a single nanocarrier. The present project aims to develop novel hybrid phospholipid-based vesicles characterized by a viscoelastic internal core. In particular, it intends to define the optimal experimental conditions for gelation of the internal core of liposomes in order to maximize the stability of the resulting hybrid nanocarrier.
This aim will be pursued encapsulating polyethylene glycol-dimethacrylate (PEG-DMA) in the fluid aqueous compartment of liposomes of different composition, with the intent to convert their liquid inner compartment into a soft and elastic hydrogel. The effect of the molecular weight of PEG-DMA on the principal properties of the hybrid nanosystems will be investigated. Varying the molecular weight of PEG-DMA also its hydrophilic/lipophilic balance will be modified, for this reason, a different localization of the polymer within the structure of liposomes and a different interaction with their membrane may be expected. Therefore, the effect of the presence of the polymer and the length of its oxyethylene chain will be carefully studied in order to have insight into the stability and permeability of gel-core liposomes respect to conventional vesicles.
Hybrid liposomes with a core composed of a physically or chemically cross-linked network have been studied for their attractive features and special properties. Different approaches have been used for the development of hydrogel-liposome assemblies. In particular, they can be obtained by anchoring the lipid bilayer on the surface of preformed hydrogels, as in lipo-beads [5-7], or by cross-linking encapsulated hydrophilic monomers inside the inner core of liposomal vesicles [8-10]. In both cases, a modified release kinetic of entrapped drugs could be obtained and, in addition, the presence of a stable polymeric scaffold provides the internal mechanical support to the liposomal membrane mimicking the elastic protein network of the cytoskeleton. However, a great difference in the dimensions of the final assemblies exists. In fact, only the second method allows preparing hybrid carriers of nanometric size and narrow size distribution, which can be used, as an alternative to conventional liposomes. These nanoconstructs can be used as nano-sized phospholipid-polymer hybrid assemblies (i.e. as such), or as nano-hydrogel after removal of the external bilayer.
These lipid-polymer nanohybrids provide a flexible platform affording ample control over their physical, chemical and biological attributes. This degree of flexibility is of the uttermost importance to bypass the numerous extracellular and intracellular biological hurdles and to provide a suitable drug delivery solution for the ever-expanding collection of pharmaceuticals and adjuvants with greatly diverging physicochemical properties. In addition, the potential of a more complex integrative drug delivery approach could come to light in the complex pathophysiology encountered in various diseases.
A lot of research has been focused on the preparation, gelation procedure and structural characterization of these core gelled liposomes, but their ability in loading drugs, and their use as pharmaceutical carriers [11] remains largely unexplored. For this reason, starting from previous studies focused on the use of liposomes as a template to create nanohydrogels [12], this project intends to create new hybrid systems investigating their ability to act as a carrier for drug delivery. Attention will be paid to the stability of the final hybrid vesicles under different conditions and under the effect of external stimuli.
[5] S. Kazakov, K. Levon, Curr. Pharm. Design 12 (2006) 4713-4728
[6] T. Jin, P. Pennefather, P.I. Lee, FEBS Lett. 397 (1996) 70-74
[7] C.C Ng, Y.L. Cheng, P.S. Pennefather, Biophys. J. 87 (2004) 323-331
[8] S. Kazakov, M. Kaholek, I. Teraoka, K. Levon, Macromolecules 35 (2002) 1911-1920
[9] T. G. Van Thienen, B. Lucas, F.M. Flesch, C.F. van Nostrum, J. Demeester, S.C. De Smedt, Macromolecules 38 (2005) 8503-8511
[10] S. Tiwari, A.K. Goyal, K. Khatri, N. Mishra, S.P. Vyas, J. Microencapsul. 26 (2009) 75-82
[11] Y. Wang, S. Tu, A.N. Pinchuk, M.P. Xiong, J. Colloid Interf. Sci. 406 (2013) 247-255
[12] S.Y. An, M.P. Ngoc Bui, Y.J. Nam, K.N. Han, C.A. Li, J. Choo, E.K. Lee, S. Katoh, Y. Kumada, G.H. Seong, J. Colloid Interf. Sci. 331 (2009) 98-103