Hybrid Lymphatic Drug Delivery Vehicles as a New Avenue for Targeted Therapy: Lymphatic Trafficking, Applications, Challenges, and Future Horizons

Abstract

Lymphatic drug targeting is an effective approach for targeting immunomodulators, and chemotherapeutic drugs at a specific organ or cellular location. The cellular, paracellular, and dendritic cell trafficking machinery are involved in the lymphatic transport of therapeutic agents. The engineering of triggered and hybrid lymphatic drug delivery systems (LDDS) is a promising strategy to fight cancer metastasis and microbial pandemics. Hybrid lymphatic drug delivery systems can be tailored and developed by grafting the conventional LDDS with biological agents. Thus, hybrid LDDS could collect the benefits of conventional and biological delivery systems. Moreover, the fabrication of triggered LDDS increases drug accumulation in the lymphatic system in the response to an internal stimulus such as pH, and redox status or external such as magnetic field, temperature, and light. Stimuli-responsive LDD systems prevent premature release of payload and mediate selective drug biodistribution. This improves therapeutic impact and reduces the systemic side effect of anticancer, immunomodulatory, and antimicrobial therapeutics. This review highlights the challenges and future horizons of nanoscaled-triggered LDDS and their influence on the lymphatic trafficking of therapeutic molecules. Graphical abstract

Assembly of nanostructured lipid carriers loaded gefitinib and simvastatin as hybrid therapy for metastatic breast cancer: Codelivery and repurposing approach

“…Therefore, the presence of a free carboxylic group could be the main contributor to erythrocyte hemolysis. In our previous study, it was found that administration of GFT at the reported dose produced a serum level below 2 µg/mL (Harisa, Sherif, & Alanazi, 2023). Moreover, the in vivo study showed that serum obtained from blood samples was clear with no notable hemolysis.…”

“…Furthermore, cancer cells escaped from the primary site (breast) to secondary organs through the lymphatic system which exaggerates the rate of death (Sherif et al, 2022b). The escaped cancer cell could be entrapped within the lymph nodes where it is considered a key sponsor of relapse following the completion of therapy (Harisa, Sherif, & Alanazi, 2023). Consequently, there is an urgent demand to establish effective approaches to overcome the developed resistance and rerouting the administered therapeutic agents to the lymphatic system (Yaghoubi et al, 2022).…”

“…The use of these carriers has great attention due to bypassing the challenges associated with traditional drug therapy (Sherif et al, 2022a). Particularly, nanoscaled lipid‐based drug cargoes are lymphotropic drug delivery systems, however, the lymph nodes are a habitat for buried cancer cells as a hot spot for cancer relapse (Harisa, Sherif, & Alanazi, 2023). Furthermore, the lymphatic system is the main channel for cancer invasion.…”

“…Furthermore, the internalization of NLC into cancer cells is quicker compared with other lipid‐based formulations (Shao et al, 2015). Moreover, lipid nanocarriers and other lipid drug cargoes could be actively uptake by low‐density lipoprotein LDL receptors (LDL‐r) that are upregulated by the cancer cells (Harisa, Sherif, & Alanazi, 2023).…”

Enhanced Codelivery of Gefitinib and Azacitidine for Treatment of Metastatic-Resistant Lung Cancer Using Biodegradable Lipid Nanoparticles

“…However, encapsulating anticancer agents within a drug delivery system capable of reaching the lymphatic system and overcoming resistance offers a promising approach to improve patient outcomes. This is attributed to the reported cancer relapse, where detached cancer cells are hidden within the lymph nodes of the lymphatic system [19] and can enter systemic circulation following therapeutic protocols, leading to the formation of new masses in systemic organs [20].…”