Lipidic Aminoglycoside Derivatives: A New Class of Immunomodulators Inducing a Potent Innate Immune Stimulation

Abstract

Development of simple and fully characterized immunomodulatory molecules is an active area of research to enhance current immunotherapies. Monophosphoryl lipid A (MPL), a nontoxic lipidic derivative from bacteria, is the first and currently only adjuvant approved in humans. However, its capacity to induce a potent response against weak immunogenic tumoral‐associated antigens remains limited. Herein, a new generation of lipidic immunomodulators to conduct a structure–activity relationship study to determine the minimal structural elements conferring immunomodulatory properties is introduced. Two lead molecules characterized by a short succinyl linker between two oleyl chains and a polar headgroup consisting of either naturally occurring tobramycin (DOST) or kanamycin (DOSK) are identified. These two lipoaminoglycosides self‐assemble in very small vesicles. In a wide variety of cells including 3D human cell culture, DOST and DOSK induce the upregulation of proinflammatory cytokines and interferon‐inducible proteins in a dose and time‐dependent manner via a caveolae‐dependent proinflammatory mechanism and phosphatidylinositol phospholipase C activation. Furthermore, after intratumoral administration, these lipoaminoglycosides induce an efficient immune response leading to significant antitumor activity in a mouse breast cancer model. Altogether, these findings indicate that DOST and DOSK are two groundbreaking synthetic lipid immunostimulators that can be used as adjuvants to enhance current immunotherapeutic treatments.

Dopamine Receptor-Mediated Binding and Cellular Uptake of Polydopamine-Coated Nanoparticles

“…Pretreatment of Neuro-2a cells with amiloride led to at least 50% reduction in cellular uptake of Au 13 @PDA 5 @PEG 1000 NPs under serum-free and serum-containing conditions (Figure S15). This observation indicates macropinocytosis as a major uptake pathway, in agreement with literature precedent. , [We verified by confocal imaging that amiloride pretreatment effectively blocked the cellular uptake of 70 kDa tetramethylrhodamine (TRITC)-labeled dextran, a common tracer of macropinocytosis, , as evidenced by significant reduction in intracellular TRITC fluorescence (Figure S16). ] Inhibition of energy-dependent endocytosis and actin by pretreatment with sodium azide and cytochalasin D significantly reduced NP uptake, but pretreatment with chlorpromazine and methyl beta-cyclodextrin did not.…”

Oxygen‐Generating Cryogels Restore T Cell Mediated Cytotoxicity in Hypoxic Tumors

“…Moving forward, innovative biomaterials such as O 2 ‐cryogels hold great potential to advance the future of cancer immunotherapy such as T cell‐based immunotherapies (e.g., CAR T cells). [ 50,51,86,87,89–91 ] Considering the clinical approval of several immune checkpoint inhibitors for cancer treatment [ 92 ] and the recent advances in targeting the hypoxia‐adenosinergic signaling pathway, [ 93 ] the combination of O 2 ‐cryogels with immune checkpoint blockade (e.g., CTLA‐4 or PD‐1) [ 17 ] should be investigated for a synergistic effect and improve these treatments. This is further supported with recent studies suggesting hypoxia as a potential obstacle on immune checkpoint inhibitors to treat cancer.…”

Aminoglycoside‐Based Biomaterials: From Material Design to Antibacterial and Gene Delivery Applications

“…[ 8 ] Through the amidation reaction, a family of lipidated aminoglycosides bearing dioleyl, distearyl, dipalmityl, dimyristyl, and cholesterol were prepared. [ 24,25 ] Besides, the aminoglycosides can also be used as monomers to synthesize hyperbranched polymers via Michael‐addition reactions [ 26 ] of the primary amine groups. [ 27,28 ] The amino groups could also perform ring opening reactions with epoxides, [ 29,30 ] affording various lipid‐modified aminoglycosides and hyperbranched aminoglycosides.…”

“…It was observed that the vesicles assembled from DOSK with a short spacer (succinyl) and a long unsaturated hydrophobic segment (dioleyl) could trigger a relative stronger upregulation of cell immunity via a caveolae‐mediated endocytosis. [ 24 ]…”