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Micromixer technology was used to prepare polymeric vesicles (Pluronic® L-121) dual loaded with the anti-cancer drug camptothecin and magnetic nanoparticles. Successful incorporation of the magnetic nanoparticles was confirmed by transmission electron microscopy. Dynamic light scattering measurements showed a relatively narrow size distribution of the hybrid polymersomes. Camptothecin polymersomes reduced the cell viability of prostate cancer cells (PC-3) measured after 72 h significantly, while drug-free polymersomes showed no cytotoxic effects. Covalent attachment of a cancer targeting peptide (bombesin) as well as a fluorescent label (Alexa Fluor® 647) to the hybrid polymersomes was performed and specific cell binding and internalization were shown by flow cytometry and confocal microscopy. Relaxometry measurements clearly demonstrated the capacity of magnetic polymersomes to generate significant T2-weighted MRI contrast and potentially allow for direct monitoring of the biodistribution of the polymersomes. Micromixer technology as an easy, fast and efficient way to manufacture hybrid polymersomes as theranostic drug delivery devices is a further step from basic research to personalized medicine.
Polymeric vesicles (Pluronic® L-121) loaded with magnetic nanoparticles (MNP) and an anti-cancer drug (camptothecin) were prepared continuously in a micro mixing device. Characterization by TEM confirmed the successful incorporation of the MNP and DLS measurements showed a relatively narrow size distribution of the hybrid polymersomes. A very high drug loading of camptothecin (100 µg/ml in the polymersome formulation) was reached and a drug release study of loaded magnetic polymersomes has shown a sustained camptothecin release over several days. Carboxylation of Pluronic® L-121 was performed and enabled a further surface functionalization with bombesin, a 14 amino acid peptide, which binds specifically to the GRPR (gastrin releasing peptide receptor). This receptor is often overexpressed in tumor cells (e.g., human prostate cancer cells) and therefore a suitable target for cancer treatment. An additional fluorescence label with Alexa Fluor® 647 allow tracking of the polymersomes e.g., in cell experiments. Relaxivity measurements to evaluate the potential of magnetic polymersomes as MR contrast agent for in vivo imaging are in progress.
Developing polymersomes for drug delivery purposes requires a deeper understanding of their behavior in physiological environment. We performed the self-assembly and in-situ loading of polybutadiene-block-polyethyleneoxide (PB-b-PEO) polymersomes in a continuous process using micromixers. Varying the length and end-groups of the starting block copolymer allows us to control the polymer membrane thickness and surface functionalities (hydroxyl or carboxylic acid), required to realize a further coupling with specific cell targeting ligands. To get a deeper understanding of these polymersomes in physiological environment, we studied the cellular response (HeLa cells) in presence of various polymersomes, and showed by cytotoxicity tests the relative biocompatibility of the systems. Flow cytometry experiments at 4?°C in PBS buffer showed a different behavior of hydroxyl-functionalized vesicles compared to carboxylic acid-functionalized vesicles. On the contrary cell binding in DMEM medium supplemented with 10% FCS was almost completely blocked with both kinds of polymersomes. Protein adsorption measurements by dynamic light scattering confirmed that protein binding occurs in all cases, which apparently influences the particle-cell interaction. This study contributes towards a deeper understanding of polymersomes in biological environment and further investigations will help us to design highly effective polymersomes for in vitro as well as in vivo applications.