The extensive use of oral dosage forms for the treatment of diseases may be linked to deficient pharmacokinetic properties. In some cases the drug is barely soluble; in others, the rapid transit of the formulation through the gastrointestinal tract (GIT) makes it difficult to achieve therapeutic levels in the organism; moreover, some drugs must act locally due to a gastric pathology, but the time they remain in the stomach is short. The use of formulations capable of improving all these parameters, as well as increasing the resident time in the stomach, has been the target of numerous research works, with low-density systems being the most promising and widely explored, however, there is further scope to improve these systems. There are a vast variety of polymeric materials used in low-density gastroretentive systems and a number of methods to improve the bioavailability of the drugs. This works aims to expedite the development of breakthrough approaches by providing an in-depth understanding of the polymeric materials currently used, both natural and synthetic, their properties, advantages, and drawbacks.

Over the past decade or so, polymerization-induced self-assembly (PISA) has become widely recognized as a powerful technology platform for the rational synthesis of sterically-stabilized diblock copolymer nano-objects in concentrated solution. In the present study, a binary mixture of water-soluble poly(glycerol monomethacrylate) (PGMA₅₉) and poly(ethylene glycol) (PEG_x, where x = 45 or 113) precursors were simultaneously chain-extended with 2-hydroxypropyl methacrylate (HPMA) using reversible addition–fragmentation chain transfer (RAFT) aqueous dispersion polymerization. For each of the two PEG blocks, a phase diagram was constructed at a fixed copolymer concentration of 10% w/w by systematically varying the target PHPMA DP (n) and the PEG mole fraction (z). The resulting diblock copolymer nano-objects are denoted using the general formula [z PEG_x + y PGMA₅₉]-PHPMA_n. Using a PEG block DP of 45 (i.e. x = 45), a pure worm phase was identified for just two diblock compositions when z = 0 (namely PGMA₅₉-PHPMA₁₅₀ and PGMA₅₉-PHPMA₁₆₀). In striking contrast, using a PEG block DP of 113 enabled twenty examples of pure worms to be obtained for z values ranging between 0.00 and 0.90. The thermoresponsive nature of these worms was assessed by tube inversion experiments and gel rheology studies. Importantly, reversible thermoresponsive behaviour was only observed when z ≤ 0.6 when targeting a PHPMA DP ≤ 180. Moreover, there was no evidence that inter-worm hydrogen bonding between the PGMA₅₉ and PEG₁₁₃ stabilizer chains leads to stronger gels. These findings are expected to inform future studies focused on evaluating the minimum hydroxyl content of such worm gels that is required to induce stasis in embryonic human stem cells (see I. Canton, et al., ACS Cent. Sci., 2016, 2, 65–74).

The experimental model design proposed herein has proved to be an indispensable tool to rapidly and easily elucidate the optimal polymerization conditions in the preparation of tailor-made responsive materials for biomedical applications. The use of reversible covalent bonds for the synthesis of new materials provides the polymer structures with novel functionalities and applications. The Diels–Alder (DA) reaction is an ideal synthetic method for the preparation of functional and responsive biomaterials under mild and undemanding conditions. The present work details the optimization of the polymerization conditions to synthesize two families of thermo-sensitive polymers, with either reduction-responsive properties or enhanced hydrophilicity. These polymers have been successfully prepared from two functional bisdiene monomers: a difurfuryl dithiodiethanol derivative (DiT-Fur, 1) and a difurfuryl-dithiothreitol derivative (DTT-Fur, 2), respectively, using the same bismaleimide (DMDOO, 3) derived from triethylene glycol in both systems. Twenty experiments were conducted and a Box–Behnken experimental design was used to evaluate the importance of temperature and the water content in terms of the polymer molecular weights (M_n, determined by ¹H NMR). In addition, the progress of the polymerizations at selected times was accurately monitored via IR spectroscopy. Higher temperatures were discarded since previous thermo-lability studies demonstrated that the retro-DA reaction could occur at temperatures as low as 50 °C. Temperature proved to be the most influential variable in the final M_n, exerting opposite effects in both systems. We envision that this experimental approach, applied to other polymerization processes, can enlighten the influence of key parameters in the final product obtained.