PLAM is a malignant tumor that is characterized by diffuse proliferation of abnormal smooth muscle fibers, and is relatively rare and refractory. Interstitial fluid is the main source of lymph fluid, and the delivery of drugs through the interstitial fluid may be more suitable than traditional blood delivery for such interstitial diseases. With the aim of increasing the amount of drugs reaching the interstitial fluid, we chose ISI as the mode of administration, on the basis of the close connection between PLAM and the interstitium[7, 8].
Since the development of modern medicine, a variety of routes of administration have been achieved, including oral and intravenous injection, but each has drawbacks. For instance, oral administration often has low bioavailability[9, 10], whereas intravenous injection can irritate systemic blood vessels or result in systemic toxicity. The new drug delivery method of ISI combined with nanoparticles was based on the hierarchical porous thick collagen bundle network in human interstitial tissue and driven by the orderly flow of interstitial fluid. The interstitial space, the primary source of lymph and a major fluid compartment in the body, has not been appreciated enough since its discovery. In 1894, Burnett reported a clinical case of a tumor growing in the intervaginal space of the optic nerve, emphasizing that the interstitial space, such as the parenchymal tissue, plays an important role in the occurrence and transformation of the disease. In recent years, the interstitial space, which is not between cells but is a macroscopically visible space within tissues through which interstitial fluid flows around the body, has received increasing attention by researchers. Jiantao Feng et al. have reported a ”green pathway” different from simple diffusion in tissue, explained by the properties of fluid flow within the interstitial space of tissue in the presence of a multiphase porous media structure. Hongyi Li et al. have used fluorescein, NMR and CT to confirm the existence of long-range transmission pathways originating from the extremities in the human body. Several years later, Petros C. Benias et al. demonstrated the microstructure of the interstitial space in bile ducts and skin, which is defined by a complex lattice of thick collagen bundles, according to electron microscopy and tissue slices. The fluid in interstitial spaces also have a different transmission direction from blood. Injecting gold nanoparticles through interstitial space channels results in a markedly different tissue distribution and metabolic processes than does intravenous injection. Treatment of diseases including breast cancer and malaria with ISI has also been investigated.
Compared with traditional oral administration, ISI can avoid a series of intestinal adverse reactions caused by oral drug delivery, and can increase the bioavailability of drugs. The bioavailability of oral preparations of rapamycin has been reported to be low, and the degree of oral absorption is greatly affected by the type of food eaten. These aspects must be considered during the administration of rapamycin to achieve steady state drug concentrations. In the intravenous injection method, the dose and volume of the drug are often relatively large, and a systemic reaction can easily occur. ISI is administered by injecting the drug into a specific sheath in the interstitium; the drug is then transported through the interstitial space, bypassing the blood vessels and liver, and reaches the lesion. The administration method of ISI was found to significantly increase rapamycin bioavailability and decrease the drug clearance rate; both aspects are important for regulating the dosage and frequency of medication. After ISI administration, the content of the drug in the pulmonary interstitial fluid and blood of mice significantly increased; this aspect is important for the treatment of PLAM diseases characterized by abnormal proliferation of smooth muscle cells outside blood vessels and lymphatic vessels. Thus, the drug concentration around the lesion was improved and maintained.
The reason of drug dosage form changes to nano-size is also based on the porous structure of the interstitial network, thus minimizing drug diffusion into the blood. Nanosized drugs are more easily recognized by macrophages and transported to lymphoid tissues. ISI is a new type of drug delivery that differs from traditional drug delivery. Notably, drugs with high binding rates to hemoglobin, such as rapamycin, are not suitable for intravenous injection. Here, we provide a new solution for the delivery of such drugs. Furthermore, studies on ISI are underway, and this delivery mode is expected to pave the way to a new research field in the near future.