## 7 The Key Parameters of Self-Assembly in Multi-Arm Polymers
### Solvophobic/Solvophilic Balance
Cryo-TEM micrograph analysis showed that the formed particles are polymersomes, due to the visual presence of thin outer membranes (Figure 13) [192]. Figure 12: Polymerization-induced self-assembly process proceeding through a dispersion-based mechanism; Adapted from [188] (Copyright 2017, American Chemical Society). The polymer mPEG2 kDa-b-(polyHis29 kDa)2 is highly buffered in the endolysosomal pH range prior to acidification and exhibits low cytotoxicity after 5 days of exposure (Figure 14). Below pH 7.4, the polymer evolved from cylindrical micelles to spherical micelles and ultimately to unimers as the pH decreased. The pH-induced structural transition of mPEG2 kDa-b-(polyHis29 kDa)2 nanostructures may be due to an increase in the weight fraction of the hydrophilic portion of mPEG2 kDa-b-(polyHis29 kDa)2 and may contribute to the disruption of the endosomal membrane. Furthermore, the hydrophilic model dye 5(6)-carboxyl fluorescein encapsulated in an aqueous polymer matrix exhibited slow and sustained release at pH 7.4 but highly accelerated release below pH 7.4, indicating the desired pH sensitivity of the system in the endosomal pH range [192]. Figure 14: **(A)** TEM micrographs of the mPEG-b-(polyHis)2 polymer nanostructures at different pH. **(B)** The critical association value (CAC) as a function of pH. **(C)** In vitro release profiles of the encapsulated CF in the polymersome at different pH. **(D,E)** Cytotoxicity of polymersomes and representative polycations against MCF7/ADR-RES and A2780/ADR cells after 5 days incubation [192] (Copyright 2012, The Royal Society of Chemistry). Figure 13: Representative Illustration of an Example of AB\({}_{3}\) Polymersome based on PEG-PAzo. The common point between both linear and multi-arm polymers is the fact that the length of the chains affects the morphology of the formed aggregates. In this regard, the work of [PERSON] et al. [192] has demonstrated that controlling the chain length ratio of diblock copolymers could influence the morphological transformation of aggregates. When the length of the hydrophilic PEO block chain is greater than that of the secondary hydrophobic block, micelles are formed. Under inverse conditions, vesicles are formed. Consequently, it is possible to control the chain length ratio of the blocks in solution, and therefore obtain various self-assembled morphologies with a controlled release function of the molecules. Furthermore, the proportion of solvophobic and solvophilic chains could affect various properties, including the size of nanoaggregates, their stability, and the critical micelle concentration (CMC). Generally, an increase in the solvophilic components leads to higher CMC in aggregates. A study conducted by [PERSON] et al. in 2016 achieved the synthesis and characterization of an amphiphilic copolymer A(AB)\({}_{3}\) polymer (where A = PCL\({}_{2800}\) and B = PEG), which utilized an oligosaccharide as a branching core combined with PEG and PCL [193]. The resulting architectures exhibited relatively low CMC values that were lower than those of linear PEG-b-PCL copolymers possessing similar hydrophilic/hydrophobic ratios. In addition, the findings suggest that increasing the hydrophilic fraction of PEG in the multi-arm structure led to a decrease in the hydrodynamic diameter from 107 to 72 nm (Figure 15), with an increase in CMC from 0.90 to 3.45 \(\upmu\)g.ml\({}^{-1}\). The collected results could be attributed to the alteration in the hydrophilic/hydrophobic ratio, which affects the solvation/desolvation of PEG and PCL in the aqueous medium. The PCL\({}_{2800}\)-(PCL\({}_{3100}\)-b-PEG\({}_{5000}\))\({}_{3}\) system was more likely to aggregate, potentially due to its larger surface area and uniform shape. Furthermore, the micelles demonstrated strong biocompatibility, and they exhibited efficient drug transport properties towards cells [193]. The choice of polymer used to form the core of a nanocarier can have a direct impact on the drug solubilization, loading capacity, and release kinetics of the carrier.