Degradation Kinetic Study of PLA Nanoparticles Aimed to Drug Delivery

Poly-Lactic Acid (PLA) is a biodegradable aliphatic polyester produced both in large and low scale. It is adopted in biomedical applications and as a row material for food packaging, bottles and consumables in general. The properties of lactic acid based polymers vary to a large extent depending on the ratio and the distribution between the two stereoisomers L and D. Even if PLA nanoparticles can be produced in different ways, the most adopted method is based on an emulsion process through which PLA is solubilized in an appropriate solvent along with drugs that have to be delivered. Though being deeply studied for many years up to now, drug delivery from degradable micro- and nanospheres is still far away from being fully understood. Many works related to the use of PLA NP for drug delivery applications, focused mainly on biocompatibility, bioavailability and in-vivo and in-vitro study, are reported in literature. Different models have been developed in order to describe the involved phenomena, such as hydrolytic breakup of the ester bond of the PLA chain backbone, diffusion of water and oligomers within the polymer matrix and drug release. Unfortunately, a systematic study which combine degradation, release features and in general the physics of the process with polymer properties and morphology is missed.

In this frame the aim of the present work is to fundamentally investigate the degradation kinetic of PLA and developed a reliable model which can be used as a tool to tune the polymer matrix properties in order to achieve the desired degradation behavior.

In the first part of the study hydrolytic degradation kinetics of low molecular weight PLA are investigated experimentally at different chain lengths and for different degree of racemization in different temperature and pH conditions. Kinetic rate coefficients have been measured as a function of the chain length, thus providing information about the detailed mechanism of the degradation reaction. In particular, starting from a polymer sample with broad molecular weight distribution, narrow fractions of PLA oligomers have been collected by semi-preparative HPLC. Such oligomers were then separately hydrolyzed in buffer solution appositively chosen to simulate different pH conditions which the polymer experiences during the delivery. The time evolution of the concentrations of both the initial polymer and all the degradation products (shorter oligomers) was then followed once more by HPLC, thus providing a comprehensive chemical picture of the reacting system. A simple model involving all possible hydrolysis reactions is finally developed and by fitting the model predictions to the experimental data, the corresponding rate coefficients are estimated as function of temperature, pH, chain length and degree of racemization. The latter data provide insights into the mechanism of the hydrolysis reaction, suggesting different reactivity of the ester group depending upon their position into the chain. Nice agreement between model and experiments are found when such dependence is included in the model.

Dealing with NPs the other fundamental aspects that have to be taken into account in order to model the particle degradation are: the diffusion of water, the loaded drugs, and short oligomers within the NPs, respectively. Thus, in the second part of this work degradation study of PLA NPs is investigated experimentally under different conditions. In particular diffusivity is investigated for PLA NPs systems once more for different polymer composition and morphology (D content) at different temperatures and pH conditions. PLA NPs are produced as already mentioned from a preformed polymer (obtained by ROP) by emulsion based method. The degradation in buffer solution at constant temperature is experimentally accessed and both degradation kinetic and particle size and morphology measurements are carried out. In particular, the time evolution of both polymer and aqueous phases is determined in terms of composition by HPLC analysis. A full model accounting for both diffusion and polymer degradation, based on the kinetic determined in the previous part, is developed and compared with experimental results. The model provide a reliable tool through which it is possible to tune and correlate polymer properties and degradation behavior.

Finally, NPs loaded with tetracycline as drug, has been studied. Degradation and drug release in PBS at 37°C is investigated and characterized involving PLA with different molecular weight. Correlation between diffusivity and the degradation process is then studied. Since it is known that tetracycline is active in preventing neurodegenerative diseases (like Parkinsons and Alzheimer diseases), the possibility that PLA NPs loaded with this drug pass the Blood Brain Barrier (BBB) is under investigation in collaboration with the Mario Negri Institute.