Traceable Nanoparticles with Spatiotemporally Controlled Release Ability for Synergistic Glioblastoma Multiforme Treatment

Abstract

Doxorubicin (DOX), one of the most widely used clinical antineoplastics, has ineffective therapeutic efficacy on glioblastoma multiforme (GBM) with extremely short survival time due to many obstacles such as blood-brain barrier (BBB), tumor angiogenesis, and glioblastoma stem cells (GSCs). To overcome, biocompatible nanoparticles named CARD-B6 loading three clinical drugs are developed. Unlike other nanomedicines, CARD-B6, with the ability of spatiotemporally controlled release, maximize the effectiveness of DOX.(1) After CARD-B6 cross the BBB via B6, combretastatin A4 that is first released via protonation of poly (β-amino ester) specifically destroys angiogenesis to facilitate the interaction between GBM and CARD-B6. (2) Internalized into glioblastoma cells later, DOX is released via the breakage of amido bond to induce apoptosis, which is facilitated by the simultaneously released all-trans retinoic acid (ATRA). (3) After endocytosis into GSCs, the rapidly released ATRA induces the GSCs differentiation and downregulates the survival pathways, which enhances the sensitivity of GSCs to the subsequently released DOX. This synergistic antitumor effect significantly extends survival time of GBM mouse model. CARD-B6 are traced by superparamagnetic iron oxide nanocubes with high r 2 relaxivity for magnetic resonance imaging. Therefore, the traceable CARD-B6 with spatiotemporally controlled release ability are emerging as a powerful platform for GBM treatment.

Antiangiogenic Targets for Glioblastoma Therapy from a Pre-Clinical Approach, Using Nanoformulations

“…Of the 24 articles identified in the Cochrane Library, no articles were included, as 16 articles were reviews, 5 were protocols, and 3 were clinical articles in the screening analysis. In total, only 27 full-text articles not duplicated were included in this systematic review [ 32 , 34 , 38 , 41 , 43 , 44 , 45 , 48 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ], as illustrated in Figure 1 .…”

“…The major tumoral cell characteristics used in the selected studies in our review are shown in Table 1 . Of 27 selected studies for this review, 19 studies (70%) [ 32 , 34 , 38 , 43 , 45 , 48 , 52 , 53 , 55 , 56 , 57 , 58 , 59 , 62 , 63 , 64 , 65 , 66 , 67 ] used tumor cells from a human source, 6 (22%) [ 41 , 51 , 54 , 60 , 61 , 68 ] used tumor cell from rats, and 3 studies (11%) [ 44 , 50 , 66 ] used cells from mice. The study by Agemy [ 66 ] used human and mice tumor cell sources and also used lentivirus H-RasV12-shp53 to induce glioma cells.…”

Current Trends in ATRA Delivery for Cancer Therapy

“…For the treatment of glioblastoma (GBM), Lu and colleagues constructed DSPE-PEG 2000 nanoparticles decorated with CARD-B6 peptide and loaded them with three different drugs, ATRA, DOX and Combretastatin A4 (CA4) [178]. B6 is a peptide with high affinity for transferrin receptors, thus allowing the entry of the DDS into the brain through the blood-brain barrier.…”

Multifunctional and Stimuli‐Responsive Magnetic Nanoparticle‐Based Delivery Systems for Biomedical Applications

“…Therefore, hypoxia‐responsive materials have recently attracted increasing attention for use in building imaging probes and drug delivery systems. Lu and coworkers reported a hypoxia‐/pH‐responsive and traceable co‐delivery system for glioblastoma multiforme (GBM) therapy and MRI . This multifunctional co‐delivery system was constructed by assembling SPIONs, targeted ligand B6‐decorated DSPE‐PEG2000, hypoxia‐/pH‐responsive PAE‐amido(A)‐AZO‐ATRA and pH‐responsive PAE‐A‐DOX.…”