Controlling the particle structure of
tumor-targeting nanomedicines in vivo remains challenging but must be achieved to control their in vivo fate and functions. Molecular bottlebrushes (MBs), where brush side chains are densely grafted from a main chain, have recently received attention as building blocks of
polymer-based
prodrugs because their rigid structure would be expected to demonstrate high structural stability in vivo. Here, we synthesized a poly(methacryloyloxyethyl
phosphorylcholine) (pMPC)-grafted molecular bottlebrush (
PCMB) conjugated with a
cancer drug,
doxorubicin (DOX), via an
acid-cleavable
hydrazone bond. A pMPC-based linear
polymer (LP) conjugated with DOX was also prepared for comparison. We confirmed the lack of structural transition in the
PCMB between before and after conjugation with DOX using small-angle light and X-ray scattering techniques, whereas the structure of LP was significantly influenced by DOX conjugation and transformed from a random-coil structure to a large agglomerate via hydrophobic interactions among DOXs. Although
PCMB-DOX and LP-DOX showed comparable tissue permeability, pharmacokinetics, and ability to accumulate in
tumor tissues, the antitumor efficacy of
PCMB-DOX was better than that of LP-DOX. This was presumably due to the formation of LP-DOX agglomerates. The diffusion of cleaved DOX would be restricted in the hydrophobic core of the agglomerate, resulting in the DOX release at the
tumor site being compromised. In contrast to LP-DOX, DOX release from
PCMB-DOX was not compromised after accumulation in
tumor tissues because it did not form such an agglomerate, resulting in the strong antitumor effect. We have demonstrated the potential of MBs as building blocks of
drug carriers and believe that these findings can contribute to the design of
polymer-based nanomedicines.