Abstract
Glioma initiating cells (GICs) function as the seed for the propagation and relapse of glioma. Designing a smart and efficient strategy to target the GICs and to suppress the multiple signaling pathways associated with stemness and chemoresistance is essential to achieving a cancer cure. Inspired by the metabolic difference in endocytosis between GICs, differentiated glioma cells, and normal cells, a tailored lipoprotein‐like nanostructure is developed to amplify their internalization into GICs through receptor‐stimulated macropinocytosis. As CXCR4 is highly expressed on GICs and glioma tumor sites, meanwhile, the activation of CXCR4 induces the receptor‐stimulated macropinocytosis pathway in GICs, this CXCR4 receptor‐stimulated lipoprotein‐like nanoparticle (SLNP) achieves efficient accumulation in GICs in vitro and in vivo. By carrying microRNA‐34a in the core, this tailored SLNP reduces sex‐determining region Y‐box 2 and Notch1 expression, powerfully inhibits GICs stemness and chemoresistance, and significantly prolongs the survival of GICs‐bearing mice. Taken together, a tailored lipoprotein‐based nanostructure realizes efficient GICs accumulation and therapeutic effect through receptor‐stimulated macropinocytosis, providing a powerful nanoplatform for RNA interference drugs to combat glioma.
Highlights
Most cancers contain a tumorigenic subpopulation, known as tumor-initiating cells (TICs), which is functionally defined by their self-renewal and differentiation ability
The stimulated lipoprotein-like nanoparticle (SLNP) loading miRNA were developed through the approach as shown in Figure 1a, miRNA-loaded CaP core was prepared through the water-in-oil microemulsion method.[22b]. Dioleoylphosphatydic acid (DOPA) was applied to coat on the surface of CaP core
In the sequence of FH38 peptide, the native SDF1 cysteineproline-cysteine linker was changed to alanine-proline-alanine (APA) to reduce its chemotactic activity and avoid the induction of cancer cells migration.[16b]. MiR34a-SLNPs were assembled via a two-step incubation procedure: miR34a-LNC was incubated with the FH27, FH29, and FH38 peptides at the ratio of 1:100 for 24 h to form the SDF1-mimic peptide-incorporated LNC, named as stimulated LNC (SLNC) (FH27-miR34a-SLNC, FH29-miR34a-SLNC, and FH38-miR34aSLNC)
Summary
Most cancers contain a tumorigenic subpopulation, known as tumor-initiating cells (TICs), which is functionally defined by their self-renewal and differentiation ability. TICs.[4] A critical metabolic adaptation in glioma and glioma with GICs stemness and drug resistance is another obstacle to initiating cells is macropinocytosis, an evolutionarily con- cancer therapy, which may be treatable with RNA interference served clathrin-independent endocytic pathway driven by therapy. With with CXCR4 and result in a full to partial function of SDF1.[15] miR34a loading, the nanoformulation efficiently inhibited the Through a structure-based study, it is known that the CXCR4- self-renewal and chemoresistant ability in GICs and sharply binding domain of SDF1 is RFFESH, while the activation prolonged the animal survival in GICs derived orthotopic mice domain is KPVSLSYR.[16] To realize efficient GICs-targeting models safely, especially when combined with chemotherapeudrug delivery, it is essential to mimic the structure of SDF1, tics (Scheme 1). SLNPs enable efficient targeting miRNA delivery to GICs via receptor-stimulated micropinocytosis to efficiently inhibit self-renewal and chemoresistance
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