In this paper, we describe the synthesis of asymmetric functional POEGMA-b-P(ST-co-VBA) copolymers in methanol, yielding in onepot polymerization a range of nanoparticle morphologies, including spherical micelles, worm-like, rod-like micelles and vesicles. The presence of the aldehyde group was then exploited to form crosslinks or to conjugate chemotherapy compounds, such as doxorubicin, via pH-breakable bonds (Schiff base or imine) directly to the preformed nanoparticles. The influence of the nanoparticle morphologies on the MCF-7 breast cancer cell line uptake was investigated using flow cytometry and confocal microscopy. Finally, the IC 50 of DOX, following nanoparticle delivery, was studied showing significant influence of the nanoparticle carrier morphology on therapeutic efficacy for breast cancer.

Nanoparticle size, surface charge and material composition are known to affect the uptake of nanoparticles by cells. However, whether nanoparticle shape affects transport across various barriers inside the cell remains unclear. Here we used pair correlation microscopy to show that polymeric nanoparticles with different shapes but identical surface chemistries moved across the various cellular barriers at different rates, ultimately defining the site of drug release. We measured how micelles, vesicles, rods and worms entered the cell and whether they escaped from the endosomal system and had access to the nucleus via the nuclear pore complex. Rods and worms, but not micelles and vesicles, entered the nucleus by passive diffusion. Improving nuclear access, for example with a nuclear localization signal, resulted in more doxorubicin release inside the nucleus and correlated with greater cytotoxicity. Our results therefore demonstrate that drug delivery across the major cellular barrier, the nuclear envelope, is important for doxorubicin efficiency and can be achieved with appropriately shaped nanoparticles.

Nanoparticles with various morphologies such as micelles, worm-like/rod-like and spherical vesicles are made using a polymerization-induced self-assembly (PISA) approach via a one-pot RAFT dispersion polymerization. On polymerization/self-assembly, we report a concurrent highly efficient loading of guest molecules within the nanoparticle structures. Different nanoparticle morphologies, such as spherical micelles, worm-like, rod-like, and spherical vesicles, are achieved by gradually increasing the number-average degree of polymerization (DPn) of the PST block via increasing polymerization times (in a poor solvent) as determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS) measurements. In parallel, a guest molecule (Nile Red) is encapsulated during the polymerization without disturbing the morphology or the polymerization kinetics.