Synthesis of pH-sensitive amphiphilic pentablock copolymers via combination of ring-opening and atom transfer radical polymerization for drug delivery

• pH-sensitive pentablock copolymers of PEG-[b-PCL-b-PAA]2 were synthesized.
• Combination of ring opening and atom transfer radical polymerizations were used.
• The composition of tri- and pentablock copolymers was controlled by changing the feed ratios of CL/PEG and ATRP time.
• The formation, size and morphology of micelles were studied by CMC, DLS and SEM techniques.
• The loading and controlled release of naproxen was investigated at pH 7.4 and at pH 4.2.

A series of poly(acrylic acid)-poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone)-poly(acrylic acid) pH-sensitive PEG-[b-PCL-b-PAA]2 pentablock copolymers were synthesized via a combination of ring-opening polymerization (ROP), atom transfer radical polymerization (ATRP) and acidolysis. First, hydroxyl-terminated PEG (Mn = 4000 g mol−1) was used as starting material and stannous octanoate (Sn(Oct)2) as a catalyst for ROP of ε-caprolactone (CL). Then, the macroinitiator transformed from PEG-[b-PCL]2 (Mn = 13,700 and 21,800 g mol−1, by GPC) in high conversion initiated ATRPs of tert-butylacrylate (tBA) to construct PEG-[b-PCL-b-PtBA]2 (Mn = 17,000–26,000 g mol−1; Mw/Mn = 1.13–1.25). Finally, the PEG-[b-PCL-b-PAA]2 was obtained via the acidolysis of the PtBA segment in PEG-[b-PCL-b-PtBA]2. The composition of triblock and pentablock copolymers was controlled by changing the feed ratios of CL/PEG in ROP and time in ATRP. The chain structures of copolymers were characterized by FT-IR, 1H NMR, and gel permeation chromatography (GPC). These copolymers are self-assembled into spherical nano size micelles in aqueous solution at pH < 4.5. The formation, size and morphology of nanomicelles were studied by scanning electron microscopy (SEM), dynamic light scattering (DLS) and by measuring the critical micelle concentration (CMC) using fluorescence spectroscopy. The loading and controlled release of naproxen as a model drug was investigated, and it was found that the total release in the buffer solution at pH 7.4 is higher than that at pH 4.2.

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