Lipid-based nanoparticles (NPs) including liposomes have been widely considered as drug delivery vehicles because of their ability to encapsulate therapeutic agents with high carrying capacity. However, their application potential is usually limited by burst drug release from liposomes due to their undesirable stability in serum. This situation has been significantly improved by using biodegradable polymeric NPs, which can release drugs at a sustained rate. Bearing in mind that small NPs have large surface/volume ration, polymeric NPs also have the concern of rapid drug diffusion and polymer hydrolysis accelerating NP degradation when they reach the size range of sub-100 nm. Therefore, the ability to make small NPs (50-100 nm) which exhibit remarkable stability and slow drug release are highly desired.

Here we describe a platform bionanotechnology that enables the formulation of targeted NPs which have merits of both lipid- and polymer-based NPs, while excluding some of their limitations. The NPs are comprised of: i) a biodegradable polymeric core which can carry bioactive drugs and release them at a sustained rate; ii) a lipid monolayer shell which can prevent the carried agents from freely diffusing out of the nanoparticle and reduce water penetration rate into the nanoparticle, thereby enhancing drug encapsulation efficiency and slowing drug release; iii) a stealth material that can allow the particles to evade recognition by immune system components and increase particle circulation half life; and iv) a targeting molecule that can bind to a unique molecular signature on cells, tissues, or organs of the body.

For example, using poly (D,Llactic-co-glycolic acid) (PLGA) as a polymeric core, lecithin monolayer (~2.5 nm) as a lipid shell, poly(ethylene glycol) (PEG) as a stealth material, and the A10 RNA aptamer which binds to the PSMA antigen on the surface of prostate cancer cells as a model aptamer targeting ligand, we developed targeted PLGA-Lecithin-PEG NPs. Particle size could be tuned within the range from 40 nm to 500 nm, accompanied with a surface zeta potential ranging from -80 mV to -30 mV. Using docetaxel (a widely used chemotherapeutics for cancers) as a model small molecule hydrophobic drug, the PLGA-Lecithin-PEG NP had drug encapsulation efficiency around 65% as contrast to 19% for the conventional PLGA-b-PEG diblock copolymer NP. In addition, less than 20% drugs were released from the NP during the first 6 hours, which holds broad promise for clinical applications. Both in vitro and in vivo results demonstrated that the attached RNA aptamer effectively targeted PLGA-Lecithin-PEG NPs to prostate cancer cells which express PSMA antigen on their plasma membrane, such as LNCaP cells.