Cancer is a major public health problem and one of the leading causes of death. However, traditional cancer therapy may damage normal cells and cause side effects. Many targeted drug delivery platforms have been developed to overcome the limitations of the free form of therapeutics and biological barriers. The commonly used cancer cell surface targets are CD44, matrix metalloproteinase-2, folate receptors, etc. Once the drug enters the cell, active delivery of the drug molecule to its final destination is still preferred. The subcellular targeting strategies include using glucocorticoid receptors for nuclear targeting, negative mitochondrial membrane potential and N-acetylgalactosaminyltransferase for Golgi apparatus targeting, etc. Therefore, the most effective way to deliver therapeutic agents is through a sequential drug delivery system that simultaneously achieves cellular- and subcellular-level targeting. The dual-targeting delivery holds great promise for improving therapeutic effects and overcoming drug resistance. This review classifies sequential drug delivery systems based on final targeted organelles. We summarize different targeting strategies and mechanisms and gave examples of each case.

Cancer develops with unexpected mutations and causes death in many patients. Among the different cancer treatment strategies, immunotherapy is promising with the benefits of high specificity and accuracy, as well as modulating immune responses. Nanomaterials can be used to formulate drug delivery carriers for targeted cancer therapy. Polymeric nanoparticles used in the clinic are biocompatible and have excellent stability. They have the potential to improve therapeutic effects while significantly reducing off-target toxicity. This review classifies smart drug delivery systems based on their components. Synthetic smart polymers used in the pharmaceutical industry, including enzyme-responsive, pH-responsive, and redox-responsive polymers, are discussed. Natural polymers derived from plants, animals, microbes, and marine organisms can also be used to construct stimuli-responsive delivery systems with excellent biocompatibility, low toxicity, and biodegradability. The applications of smart or stimuli-responsive polymers in cancer immunotherapies are discussed in this systemic review. We summarize different delivery strategies and mechanisms that can be used in cancer immunotherapy and give examples of each case.

Breast cancer is the most commonly diagnosed cancer in women. Resveratrol, a naturally occurring phytochemical, shows great promise in developing novel anti-cancer therapies. This study hypothesized that the mitochondria-targeted delivery of resveratrol would increase its potency and induce mitochondria-mediated apoptosis. The targeted delivery of resveratrol was achieved by conjugating resveratrol to triphenylphosphonium (TPP). The anti-cancer effects of TPP-resveratrol were studied in the murine breast cancer 4T1 and the human breast cancer MDA-MB-231 cell lines. Flow cytometry was used to study apoptosis induction, cell cycle arrest, and mitochondrial membrane potential loss. The morphological changes in the mitochondria in MDA-MB-231 cells after TPP-resveratrol treatments were examined using transmission electron microscopy. Moreover, the changes in MDA-MB-231 cell metabolism after resveratrol and TPP-resveratrol treatments were studied using metabolomic analysis. We demonstrate that TPP-resveratrol significantly improved cytotoxicity in 4T1 cells and MDA-MB-231 cells by inducing apoptosis and mitochondrial membrane potential loss. Swollen and vacuolated mitochondria were observed after the TPP-resveratrol treatment. Meanwhile, TPP-resveratrol treatment down-regulated amino acid and energy metabolism and caused the dysfunction of purine and pyrimidine metabolism. Our results provide evidence supporting the targeted delivery of resveratrol to mitochondria and suggest that TPP-resveratrol may be an effective agent for breast cancer treatment.