Length effect of stimuli-responsive block copolymer prodrug filomicelles on drug delivery efficiency

Filomicelles possess some unique properties for improved in vivo drug delivery efficiency relative to commonly used spherical nanocarriers, which have attracted great interests. However, the length effect of the block copolymer prodrug-based filomicelles with a comparable cross-section diameter on the drug delivery efficiency and antitumor efficacy still need to be systematically studied. In this report, we prepare three optimized nanoparticles with a comparable cross-section diameter of ~40 nm, including long filomicelles (LFMs) with the length of ~2.5 μm, short filomicelles (SFMs) with the length of ~180 nm, and spherical micelles (SMs) with a diameter of ~40 nm. All of them are self-assembled from the pH and oxidation dual-responsive block copolymer prodrug, PEG-b-P(CPTKMA-co-PEMA), consisting of poly(ethylene glycol) (PEG) and a copolymerized block of thioketal-linked camptothecin methacrylate (CPTKMA) and 2-(pentamethyleneimino) ethyl methacrylate (PEMA). At pH 6.5, the nanoparticles are positively charged due to the protonation of PPEMA segments. Among them, SFMs are demonstrated to be internalized into cells most efficiently at pH 6.5 due to larger interaction areas with cell membranes relative to SMs. Moreover, SFMs show prolonged blood circulation similar to SMs as well as deepest tumor penetration and best antitumor efficacy among the three nanoparticles. LFMs show worst in vivo performance because their too long structure limits the cellular uptake and tumor accumulation. Therefore, the responsive polymer prodrug filomicelles with an optimized length show great potentials to overcome the physiological barriers and improve the drug delivery efficiency.