Among the various delivery strategies in
Among the various delivery strategies in the field of nano-DDS, developing smart targeted nanocarriers has long been a research focus for pharmaceutical scientists11., 12.. The ideal drug delivery outcome must be precisely delivering the therapeutic agents to their sites of action, especially for anticancer drug delivery12., 13., 14.. Since most chemotherapeutic agents are cytotoxic compounds, which inevitably impose toxicity to the normal tissues, rational design of advanced nano-DDS with high efficiency and low toxicity is crucially important for anticancer drug delivery. There is also encouraging results for the prospects of nano-DDS targeting to the intestinal dizocilpine site or specific organs (e.g., brain). These can significantly facilitate oral absorption or drug permeation of the bloodbrain barriers (BBB)16., 17., 18., 19..
Traditional targeting strategies have mainly focused on modifying ligands on the surface of nano-DDS to recognize and interact with the specific receptors on cell membrane. So far, the strategy seems to be working, but the targeting efficacy has been greatly limited by the variability and heterogeneity of membrane receptors21., 22., 23.. Different patients with same disease may have different expression levels of receptors, and different receptors levels may also be found at different stages of the disease even for the same patient. Therefore, receptor-based targeting strategies have not been brought to clinics, and it is necessary to seek for new target sites to develop targeted nanocarriers. Recently, membrane transporters have become emerging target sites for efficient drug delivery24., 25., 26., 27.. Transporters for glucose, amino acids, vitamins and ions are essential for cell nutrition. In addition to these essential nutrients, transporters could also interact with a variety of drugs, thereby affecting the efficacy and safety of drugs. Due to the important roles for cell nutrition, the expression levels of transporters are less variable than those of receptors26., 27.. In some specific cases, such as in tumors, the expression level transporters are usually upregulated to meet the enormous nutrition demand for uncontrolled growth of tumor cells. Thus, transporters are an emerging target for designing tumor-targeting nano-DDS.
In the latest decades, the application of membrane transporters was not restricted to cancer therapy. Transporter-based drug delivery strategies have also been widely investigated in oral drug delivery and brain-targeting therapy24., 25., 26., 27.. Transporter-targeted prodrug strategies have been widely investigated, and several excellent relevant reviews have been published. Herein, we outline the recent advances in transporter-targeted nano-DDS (Fig. 1), including (i) emerging transporter-targeted nano-DDS developed to facilitate oral drug delivery; (ii) recent advances in transporter-assisted brain-targeting nano-DDS; (iii) recent developments in transporter-mediated tumor-targeting drug delivery; and (iv) possible transport mechanisms involved in transporter-mediated endocytosis.
Transporter-targeted nano-DDS to improve oral absorption Oral drug delivery has long been considered a natural and safe administration route, due to its good compliance16., 28., 29., 30.. However, a wide range of drugs cannot be administrated orally, since multiple barriers may be encountered during oral absorption process. These include water insolubility, inferior stability, poor drug permeability, and complex gastroenteric environments (e.g., pH and metabolic enzymes). For example, the successful oral delivery of insulin would be profoundly important for diabetic patients, but orally-administered insulin has poor stability, resulting in inefficient oral absorption. Furthermore, developing new strategies to facilitate the intravenous-to-oral switch in cancer chemotherapy has also attracted increasing attention. In recent years, great progress has been made in designing transporter-targeted nano-DDS to improve oral absorption of peptide drugs and anticancer drugs16., 32..