Molecular Design of\nPhthalocyanine-Based Drug Coassembly\nwith Tailored Function

Coassemblies with tailored functions, such as drug loading,\ntissue\ntargeting and releasing, therapeutic and/or imaging purposes, and\nso on, have been widely studied and applied in biomedicine. <i>De novo</i> design of these coassemblies hinges on an integrated\napproach involving synergy between various design strategies, ranging\nfrom structure screening of combinations of “phthalocyanine-chemotherapeutic\ndrug” molecules for molecular scaffolds, exploration of related\nfabrication principles to verification of intended activity of specific\ndesigns. Here, we propose an integrated approach combining computation\nand experiments to design from scratch coassembled nanoparticles.\nThis nanocoassembly, termed NanoPC here, consists of phthalocyanine-based\nscaffolds hosting chemotherapeutic drugs, aimed at hypersensitive\nchemotherapy guided by photoimaging for targeting tumors. Our design\nstarts from the selection of phthalocyanine derivatives that are not\naggregation-prone, followed by computational screening of coassembled\nmolecules covering various categories of chemotherapy drugs. To facilitate\nan efficient and accurate assessment of coassembly capabilities, we\nutilize small systems as surrogates to enable free-energy calculations\nat all-atom levels facilitated with enhanced sampling and statistical\nmechanics for efficient and accurate evaluation of coassembly ability.\nThe final top NanoPC candidate, comprised of phthalocyanine PcL and\ncytarabine (CYT), can greatly increase the fluorescence intensity\nratio of tumor/liver by 21.5 times and achieve higher antitumor efficiency\nin a pH-dependent manner. Therefore, the designing approach proposed\nhere has a potential pattern, which can provide ideas and references\nfor the design and development of coassembled nanodrugs with tailored\nfunctions and applications in biomedicine.