Molecular Design of Phthalocyanine-Based Drug Coassembly with Tailored Function

Coassemblies with tailored functions, such as drug loading, tissue targeting and releasing, therapeutic and/or imaging purposes, and so on, have been widely studied and applied in biomedicine. De novo design of these coassemblies hinges on an integrated approach involving synergy between various design strategies, ranging from structure screening of combinations of “phthalocyanine-chemotherapeutic drug” molecules for molecular scaffolds, exploration of related fabrication principles to verification of intended activity of specific designs. Here, we propose an integrated approach combining computation and experiments to design from scratch coassembled nanoparticles. This nanocoassembly, termed NanoPC here, consists of phthalocyanine-based scaffolds hosting chemotherapeutic drugs, aimed at hypersensitive chemotherapy guided by photoimaging for targeting tumors. Our design starts from the selection of phthalocyanine derivatives that are not aggregation-prone, followed by computational screening of coassembled molecules covering various categories of chemotherapy drugs. To facilitate an efficient and accurate assessment of coassembly capabilities, we utilize small systems as surrogates to enable free-energy calculations at all-atom levels facilitated with enhanced sampling and statistical mechanics for efficient and accurate evaluation of coassembly ability. The final top NanoPC candidate, comprised of phthalocyanine PcL and cytarabine (CYT), can greatly increase the fluorescence intensity ratio of tumor/liver by 21.5 times and achieve higher antitumor efficiency in a pH-dependent manner. Therefore, the designing approach proposed here has a potential pattern, which can provide ideas and references for the design and development of coassembled nanodrugs with tailored functions and applications in biomedicine.