Novel Degradable Ultrasmall Nanoparticles and Their Application in Drug Delivery

Poly(lactic acid) (PLA) nanoparticles are considered effective devices for drug delivery and targeting, mainly because of their degradable/biocompatible nature of the polymer along with the suitable particle size. The four major parameters assessing the quality of polymer particles for drug delivery applications are: particle size, encapsulation efficiency, surface charge, and release behavior[1]. There are lots of methods to prepare PLA particles of colloidal size, such as nanoprecipitation, emulsion-based methods, salting-out methods, spray drying, and so on[2]. However, the minimum particle size produced through anyone of the above techniques is around 100 nm.

The aim of this work is to assess a new approach to the synthesis of PLA particles with smaller size. Through ring-opening polymerization of L,L-Lactide using Sn(Oct)₂ as catalyst and suitable co-catalysts, poly(lactic acid) chains are grown and functionalized. Starting from these functionalized oligomers and applying conventional emulsion polymerization process, very small PLA-based, fully degradable nanoparticles with size as small as 15 nm are synthesized. Meanwhile, extremely narrow particle distributions have been also obtained.

The degradation study has been carried out using different particles in terms of size and PLA chain length as well. The rates of degradation and release of lactic acid and its oligomers from the nanoparticles have been measured by high performance liquid chromatography (HPLC)[4]. The complete degradation kinetics of the PLA-block of the polymer chains has been studied. Moreover, a relation between the time of complete degradation (particle disappearance) and the corresponding polymer molecular weight has been determined. Finally, the biocompatibility of these particles has been proved by in vitro tests. The nanoparticles stabilized by TWEEN80 have been incubated with U266 myeloma cell line at 37 °C. The time-increasing viable cell counts and the high viability of the cells at the end of the incubation prove that these particles are non-toxic.

Such ultra-small nanoparticles are very promising for special drug delivery applications. In particular they can be used to enhance the cellular uptake and to increase the membrane passage, especially the blood brain barrier (BBB). Similar studies are currently on going in collaboration with the Institute for Pharmacological Research Mario Negri (Milano, Italy).

[1] Hans, M.L., Lowman, A.M., Curr. Opin. Solid State Mater. Sci., 2002, 6, 319-327.

[2] Lassalle, V., Ferreira, M., Macromol. Biosci. 2007, 7, 767-783.

[3] Pending patent.

[4] Codari, F., Moscatelli, D., Storti, G., Morbidelli, M., Maromol. Mat. Eng, 2010, 1, 58.