Nanotechnology is widely used in targeted drug delivery, but different drug delivery systems need to \'re-determine\' different synthesis schemes, which greatly limits the further expansion of targeted nanomedicine applications. In this study, we propose a facile and versatile modular stacking strategy to fabricate targeted drug delivery systems to enable tailored designs for patient-specific therapeutic responses. The systems were constructed by a pH-sensitive prodrug module and a mitochondrial targeting module via self-assembly. Using this modular strategy, we successfully prepared two targeting nano-drug delivery systems, TPP-DOX and PK-DOX, where the mitochondrial targeting molecules were triphenylphosphonium (TPP) and 1-(2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195), respectively. Confocal laser microscopy and flow cytometry tests revealed that TPP-DOX and PK-DOX exhibited high mitochondria targeting capability and greatly improved the drug retention in drug-resistant cells. The antitumor activity tests showed that the IC50 values of TPP-DOX and PK-DOX in MCF-7/ADR cells were 2.5- and 8.2-fold lower than that of free DOX, respectively. These results indicated that PK was more effective than TPP. The studies on their therapeutic effects on human breast cancer resistant cells verified the feasibility of the modular approach, indicated that the two modular targeted drug delivery systems: (1) retain the drug toxicity and cell-killing effect of the prodrug module, (2) have precise targeting capabilities due to mitochondrial targeting module, (3) enhance drug uptake, reduce drug efflux and reverse the multidrug resistance effect to a certain extent. The results show that modular stacking is a practical, effective and versatile method for preparing targeting drugs with broad application prospects. This study provides an easy approach on preparing customizable targeted drug delivery systems to improve precision therapies.

The superiority of nanomedicine over conventional medicines in the treatment of cancer has gained immediate recognition worldwide. As traditional cancer therapies are nonspecific and detrimental to healthy cells, the ability of nanomedicine to release drugs to target tumor cells specifically instead of healthy cells has brought new hope to cancer patients. This review focuses on the effects of various factors of nanoparticles such as transport, concentration in cells, tumor microenvironment, interaction with protein, penetration, uptake by tumor cells, cancer cell mutations, and intracellular trafficking of the nanoparticle. Besides the history of nanomedicine, future perspectives of nanomedicines are also explored in this text.