Polymer prodrugs have attracted intense interest in tumor chemotherapy [1], [2], [3], owing to their better on-demand drug release in comparison with those drug delivery systems (DDSs) via non-covalent drug-loading, which usually show obvious premature drug leakage. However, the conventional polymer prodrug-based nanomedicines are not so stable upon dilution, due to the critical micelle concentration (CMC). It is to say, the supramolecular micelles would demicellize once they enter the bloodstream via intravenous injection, causing toxic side effects.

Unimolecular micelles have been recognized as a promising candidate to solve the above problem [4], [5], [6], owing to their superior stability. For the unimolecular micelles based on the uniform spherical topology-structured polymers, such as hyperbranched (co)polymers [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27] or dendritic (co)polymers [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], the chemotherapeutic drugs could be loaded into their inner cavities [8], [9], [10], [11], [12], [13], [14], [15], [16], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42] or conjugated onto their surface functional groups via dynamic covalent bonds which could be cleaved off responding to the lower intracellular acidity [17], [18], [19], [20], [21], [22], [23], [43], [44] or higher intracellular glutathione (GSH) level [24], [25], [26], [27].

It was found that the hydrophilic-hydrophobic property of the unimolecular micelles played an important role in the drug release performance of the DDSs via either covalent drug-loading or covalent conjugating [31]. For examples, the hydrophobic drugs could be stably encapsulated into the unimolecular micelles with highly hydrophobic cores, they could hardly be released [33]. While the lowly hydrophobic cores led to a significant premature drug leakage before cellular internalization [40].

As for the prodrug unimolecular micelles in which the hydrophobic drugs were conjugated onto the surface functional groups of the highly hydrophobic cores, the hydrophobic drugs were actually embedded into the skin layer of the highly hydrophobic cores. Even the dynamic covalent conjugation was cleaved, the released drugs could not be released but still encapsulated in the highly hydrophobic cores of the unimolecular micelles [43].

To avoid the leakage of the lowly hydrophobic drug noncovalently lodaded in the cavities in the unimolecular micelles and the encapsulation of the released highly hydrophobic drug which was conjugated on the surface of the hydrophobic core in the unimolecular micelles, CPT@DOX-DPUTEA-PEG nanomedicine was designed for combination chemotherapy by conjugating DOX on the surface functional groups of the pH-responsive dendritic polyurethane (DPUTEA) cores in the PEGylated pH-responsive dendritic polyurethane (DPUTEA-PEG), followed by encapsulating CPT in their inner cavities (Scheme 1). The synergistic controlled drug release effect was found in the proposed CPT@DOX-DPUTEA-PEG nanomedicine, resulting a better co-delivery performance.