Functional self-assembled poly (L-lactide) nanoparticles for targeted delivery of bioactive agents.

摘要

Self-assembled nanoparticles (NPs) have been used extensively in clinical applications. Their small size makes them potentially useful for targeted delivery of bioactive agents, and particles less than 200 nm in size will be readily uptaken by cells. NPs can be modified with functional groups to enhance their biological specificity. These characteristics make the NPs an ideal carrier for applications such as bone tissue regeneration and cancer therapy. Bone diseases and cancer affect millions of people each year, and current treatments present limitations due to costs, side effects, and lack of compatibility. This work will focus on the applications of self-assembled NPs with different functionalities for sustained delivery of growth factors in bone regeneration and targeted delivery of chemotherapeutic agents in cancer therapy.In the first part, poly(lactide-co-glycolide) fumarate (PLGF) NPs were used for the delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2) and a peptide isolated from the BMP-2 protein. They were encapsulated in or grafted to the NPs for their sustained release. Bone marrow stromal cells incubated with the rhBMP-2 protein or BMP-2 peptide increased the mineral content and the expression level of osteogenic markers such as osteopontin and osteocalcin, and vasculogenic markers such as Pecam1. This demonstrated that a sustained release of the BMP-2 from the NPs results in a higher expression of osteogenic/vasculogenic cascade, as compared with a single dosage of free BMP-2.In the second part, NPs were used for the delivery of Doxorubicin (DOX), which is used in the treatment of breast cancer. NPs smaller than 150 nm in diameter and with narrow size distribution were self-assembled in solution. Incubation of tumor cells with NPs encapsulating DOX showed a significant decrease in the viability of tumor cells compared to the free drug. This uptake was confirmed with fluorescently labeled NPs with up to 70% uptake after 24 hours. The uptake was facilitated by the self-assembled nature of the macromer. Migration of tumor cells was significantly reduced by encapsulation of the drug in self-assembled NPs. Uptake by the cells increases drug concentration inside them and encapsulation allows for a sustained release while protecting the drug from degradation. Engineered self-assembled NPs have the potential to be used for future clinical implementation in bone repair and to improve cancer therapy.