Interrogation of Folic Acid-Functionalized Nanomedicines: The Regulatory Roles of Plasma Proteins Reexamined

Abstract

Folic acid (FA) has been extensively exploited to facilitate targeted delivery of nanomedicines by recognizing the folate receptor-α (FR-α) overexpressed in many human cancers. Unfortunately, none have been approved for clinical use yet. Here we reveal that FA functionalization induces heavy natural IgM absorption on the liposomal surface, depriving FA of receptor recognition and accelerating complement activation in vivo. FA functionalization does not enhance distribution of liposomes in FR-α-overexpressed tumors in comparison to plain liposomes (without FA), but leads to aggravated capture of liposomes by macrophages in the tumor, liver, and spleen. In addition, FA-functionalized polymeric nanoparticles are also vulnerable to natural IgM absorption. This work highlights the pivotal roles of natural IgM in regulating in vivo delivery of FA-functionalized nanomedicines. Due to the prevalent association of immune disorders and varying levels of immunoglobulins with cancer patients, extraordinary cautiousness is urged for clinical translation of FA-enabled targeted delivery systems.

Multiple-mRNA-controlled and heat-driven drug release from gold nanocages in targeted chemo-photothermal therapy for tumors

“…For both diagnostic and therapeutic applications, it is critical to selectively drug release to increase the drug cellular uptake in cancer cells and decrease the overall dosage, targeted molecules should be combined with the drug carrier. A number of ligands that selectively bind tissue-associated biomolecules (receptor) have been explored for drug delivery, including antibody 17 , folate 18,19 , DNA or RNA to recognize cancer marker 20 . However, most receptors of cancer cell expression are often occurs in normal cells, therefore a single ligand-receptor drug carrier potentially results in strong toxicity to normal cells, which decrease the drug efficacy and limits their biomedical applications [21][22][23][24] .…”

Photocatalytic Quantum Dot‐Armed Bacteriophage for Combating Drug‐Resistant Bacterial Infection

“…In vivo fluorescence imaging of the infected wounds revealed bacterial intensity during treatment (Figure 4c ). [ 23 ] We noticed very large areas of high fluorescence intensity on day 1, which again indicated the successful in vivo establishment of GFP ‐P. aeruginosa wound infection.…”

An Intelligent Nanovehicle Armed with Multifunctional Navigation for Precise Delivery of Toll‐Like Receptor 7/8 Agonist and Immunogenic Cell Death Amplifiers to Eliminate Solid Tumors and Trigger Durable Antitumor Immunity

“…proposed that the poor targeting efficiency of FA‐functionalized nanoparticles can be ascribed to natural IgM absorption on the surface of nanoparticles (e.g., liposomes and polymeric nanoparticles), depriving FA of receptor recognition and accelerating complement activation in vivo. [ 25 ] Indeed, we observed no difference in the uptake of F/IMI@CuS or IMI@CuS by FA receptor‐positive cells (tumor cells) upon intravenous injection (i.v. ), which is in agreement with previous reports.…”

“…), which is in agreement with previous reports. [ 25 ] Additionally, in both cases, no significant variation in IR820 signal was observed in FA receptor‐negative cells (immune cells, for example, DCs, macrophages, and T cells) (Figure S13A–E, Supporting Information). These data demonstrate that the binding of FA to its receptor could be influenced by the route of administration, and local intratumoral administration with FA‐targeting could be an optimal choice to prevent this influence.…”