Table 4.
Antiangiogenic therapeutic process for glioblastoma.
| Ref. | Therapy Type (NP: Formulations) |
Therapeutic Target | Route/Local of Administration | Frequency- Dose (mg/Kg) |
Vehicle | Time Point of Therapy | Tumoral Reduction | Follow-Up Evaluation after Induction | Therapeutic Evaluation Techniques |
|---|---|---|---|---|---|---|---|---|---|
| Wu et al. [50] | Drug delivery (Lut/Fa-PEG-PCL) |
Signal transduction pathways thar regulates tumor activities | Tail vein | Daily 50 |
Saline | 5th to 13th day | NR | 5th to 13th day (each 2 days) -Until cachexia of the mouse appeared | FLI; TUNNEL assay; Survival curve |
| Sousa et al. [32] | Drug delivery (Beva-loaded PLGA NP) |
VEGF | Intranasal | Weekly 5 |
NR | 10th; 17th day | ~46% at 24th day | 10th, 17th and 24th days | BLI |
| Clavreul et al. [34] | CED (SFN-LNCs) |
RTKs (VEGFR-2; VEGRF-3, PDGFR-β, c-kit e Flt-3); Intracellular serine /threonine kinases (Raf-1; B-Raf; B-Raf-mut) | Intratumoral | Single 3.5 µg/mouse |
Transcutol®HP (0.7 g) | 9th day | No reduction at 13th and 16th day |
13th and 16th days | MRI; H&E |
| Sun et al. [51] | Dual-targeting drug delivery (AP1-DOX-NP) |
IL-4R | Tail vein | Every other day 10 |
PBS | 10th, 12th, 14th, 16th days | NR | 3 and 24 h and 47 days | FLI; H&E; Survival curve |
| Séhédic et al. [52] | CED (12G5-LNC188Re) |
CXCR4; Signaling pathways (PI3K/Akt and MAP-kinases); Activation of MMPs; CD11b+ myeloid cells | Intratumoral | Single 10 µL/mouse |
Saline | 12th day | ~100% after 24 days | 12th, 17th, 19th to 100 days | MRI; IF; Western Blot; Survival curve |
| Lu et al. [53] | Drug delivery (CARD-B6) |
GBM microenvironment; Transferrin receptors; Telomerase activity | Intravenous | Every other day 0.5 CA4+2.5 DOX+ 0.5 ATRA |
PBS | 16th to 32nd day | NR | 12, 24, 36, 48 h, 30th and 36th day |
MRI; LSCA; TUNNEL assay; Survival curve |
| Xu et al. [54] | Drug delivery (DTX-NPs-dBECM) |
GBM microenvironment | Intratumoral | Single 800 µg/mL-DTX+ 10 mg/mL-dBECM |
Saline | 7th day | ~98% at 28th day | 7th to 28th days (weekly) | MRI; FLI-ex vivo; H&E; TUNNEL assay; Survival curve |
| Wang et al. [55] | Systemic therapy (H–S–R NPs1) |
Integrin αvβ3 on endothelium; EphA2 Tyrosine kinase receptor on tumor cells and tumor vasculature |
Tail vein | Every 2 days NR |
Saline | Started when the tumors were visible by BLI | ~99% at 12th day | 0, 4th, 8th, 12th day; 26th day |
BLI; FLI Survival curve; |
| Lin et al. [56] | Drug delivery (L-BSA NPs) |
SPARC; gp60 | Tail vein | Daily PTX/ 4-HPR, 2 each |
PBS | Started with tumor size (100−200 mm3) for 2 days | ~93% at 16th day | 0, 7 and 16 days; 37th day |
BLI; Western Blot; TUNNEL assay; Survival curve |
| Lin et al. [57] | Systemic therapy (CRLX101) |
Topo I inhibition; Hypoxia cascade (CA IX, HIF-1α, VEGF) | NR | Weekly 10 |
NR | 4th and 11th day | NR | 20th and 32nd day | H&E; TUNNEL assay; Survival curve |
| Kuang et al. [58] | Targeted drug delivery (DGL-PEG-T7/shVEGF-DOX) |
Transferrin receptor; VEGF gene; Topo II inhibition | Intravenous | Every 2 days 50 µg+8 µg DOX/mouse |
Saline | 12th, 15th, 18th day | ~80% after 18th day | 12th and 21st day | BLI; TUNNEL assay; Survival curve |
| Hu et al. [59] | Dual-targeting drug delivery (AC-NP-PTX) |
HSPG; NRP-1 | Intravenous | Every 3 days 5 |
Saline | NR | NR | 51st day | FLI; IF; Survival curve |
| Hu et al. [60] | Dual-targeting drug delivery (MSN-DOX-PDA-NGR) |
CD13 | Tail vein | Every 3 days 5 |
Saline | 5, 8, 11, 14 days | NR | 5th, 10th, 17th, 32nd day | H&E; TUNNEL assay; FLI; MVD; Survival curve |
| Banerjee et al. [61] | Targeted drug delivery (PSM) |
SSTR2 | Intravenous | Daily 2 |
Saline | 2 weeks | NR | 15th and 36th day | H&E; Survival curve |
| Zhang et al. [45] | Targeted drug delivery (Functional targeting epirubicin liposomes) |
Glut1 on BBB; GBM integrin receptors and neovasculature | Tail vein | Every 3 days 100 µg/Kg |
Saline | 14th, 18th day | NR | 20th and 28th day | FM; Survival curve |
| Feng et al. [62] | Drug delivery (CooP-NP-PTX) |
MDGI (H-FABP/ FABP3) | Intravenous | Every 3 days 5 |
Saline | 2 weeks | NR | 47.5 | H&E; Survival curve |
| Costa et al. [44] | Multimodal gene therapy(CTX-coupled SNALPs) | miR-21 (inhibits PDCD4); RhoB; p53; TGF-β; mitochondrial apoptotic networks | Tail vein/ oral |
Single 2.5/ 3 days 30 |
Saline | 13th day/ 13th, 14th, 15th day |
~45% at 17th day | 17th and 30th day | H&E; Western blot; Survival curve |
| Bechet et al. [63] | Photodynamic therapy (NP-TPC-ATWLPPR) |
VEGF receptor; NRP-1 | Tail vein | Single 2.8 (1.75 µmol/kg) |
NR | NR | ~50% after 6 days of iPDT | 4th, 6th, 10th day after iPDT | MRI; PET-CT; H&E |
| Gao et al. [41] | Dual-targeting drug delivery (DTX-IRNPs) | Integrin αvβ3 on endothelium; IL13Rα2 | Tail vein | Every 3 days 6 |
Saline | 10th, 11th, 12th day | ~71% at 17th day | 13tn, 17th, 35th day | IF; H&E; Survavil curve |
| Wojton et al. [64] | Systemic therapy (SapC-DOPS nanovesicles) |
PtdSer | Tail vein | Single 12-SapC 4.6-DOPS |
PBS | 10th day | NR | 11th, 12th, 17th day | IF; H&E; Survival currve |
| Janic et al. [65] | Cell therapy (FePro) |
CD34; AC133; SDF-1-CXCR4 signaling pathway | Intravenous | Single 10 × 106 |
PBS | 12th day | NR | 18th day | MRI; Prussian Blue |
| Day et al. [48] | Photothermal therapy (VEGF-NS) |
Integrin αvβ3 on endothelium; VEGFR-2 | Tail vein | Single 4.35 × 1010 VEGF-NS/mouse |
Saline | When tumor reached 3–5 mm | NR | 24 h and 3 days after treatment | Intravital microscopy images; H&E; Survival curve |
| Verreault et al. [43] | Drug delivery (Liposomal Irinophore CTM) |
GBM microenvironment; GBM vasculature | Intravenous | Weekly 25 Irinophore CTM; 15 Caelyx®; 2 liposomal vincristine |
PBS | 21st; 28th; 35th day | ~70% at 42nd day | 42nd day | H&E |
| Agemy et al. [66] | Systemic therapy (Iron Oxide Nanoworms- CGKRKD(KLAKLAK)2) |
Peptides homing to epidermal tumors; GBM vasculature; mitochondrial membrane | Intravenous (U87-MG) |
Every other day 5 |
PBS | 3 weeks | NR | 5–6 h after the injection | IF; Survival curve |
| Intravenous (005) |
Every other day 5 |
PBS | 10th, 12th, 14th, 16th, 18th, 20th, 22nd 24th, 26th, 28th, 30th day | NR | 5–6 h after the injection | IF; Survival curve | |||
| Intravenous (Sphere) |
Every other day 5 |
PBS | 3 weeks | NR | 5–6 h after the injection | IF | |||
| Intravenous (Lentiviral) |
Every other day 5 |
PSB | 21st, 23th, 25th, 27th, 29th, 31st, 33th, 35th, 37th day | NR | 21st, 28th, 35th day | BLI; H&E; IF; Survival curve | |||
| Ding et al. [67] | Systemic therapy (P/LLL/AON/Hu/Ms, P/LOEt/AON/Hu/Ms) |
Laminin α4 and β1 chain | Intravenous | Single 5 |
PBS | 21st day | ~91% NR day | NR | IF; H&E |
| Hekmatara et al. [68] | Drug delivery (DOX-np) |
Endothelial cells | Tail vein | Dayly 1.5 |
NR | 2nd, 5th, 8th day | ~100% at 14th day | 10th, 14th, 18th day | H&E; IMC |
| Saito et al. [38] | CED (Ls-TPT) |
Topo I inhibition; GBM vasculature | Intratumoral | Single (0.5 mg /mL; 20 μL) |
NR | 10th day | NR | 17th, 19th day | H&E; Survival curve |
Abbreviations—NR: Not Reported; Lut: luteolina; Fa-PEG-PCL: folic acid modified poly(ethylene glycol)-poly(e-caprolactone); Beva: Bevacizumab; PLGA: Poly(D,L-lactic-co-glycolic) acid; NP: Nanoparticles; CED: Convection-Enhanced Delivery; SFN: Sorafenib; LNCs: lipid nanocapsules; AP1: CRKRLDRNC peptide; DOX: Doxorubicin; AP1-DOX-NP: tumor homing peptide and DOX-loaded PLA nanoparticles; LNC: Lipid nanocapsules; 12G5: (CD184, #555971, BD Pharmingen); 188Re: Rhenium-188; CARD: nanoparticles with B6 loading three drugs ((CA4+AZO-ATRA+DOX+SPIONs)NPs); B6: peptide motif B6 (1,2-dioleoylsn-glycero-3-phosphoethan-olamine-n-[poly (ethylene glycol)] 2000 (DSPE-PEG2000)); CA4: Combretastin A4; AZO: Azobenzene; ATRA: All-trans retinoic acid; SPIONs: superparamagnetic iron oxide nanocubes; DTX: Docetaxel; DTX-NPs: Docetaxel-loaded nanoparticles; dBECM: decellularized brain extracellular matrix; H-S-R NPs1: heparin-containing NPs with two ligands (SWL and cRGD); L-BSA: LMWP (sequence: CVSRRRRRRGGRRRR)– BSA; BSA: Bovine Serum Albumin; L-BSA NPs: LMWP-modified BSA nanoparticles; LMWP: Low molecular weight protamine; CRLX101: nanoparticle-drug conjugate (NDC), containing approximately 10 wt% CPT conjugated to a linear, cyclodextrin-polyethylene glycol (CD-PEG) copolymer; DGL-PEG: dendrigraft poly-L-lysines; T7: peptide T7 (sequence His-Ala-Lle-Tyr-Pro-Arg-His); shVEGF: inhibition of endogenous VEGF mRNA; DOX: Doxorubicin; AC-NP: ATWLPPR and CGKRK peptide dual-decorated nanoparticulate DDS; PTX: Paclitaxel; MSN: Mesoporous Silica Nanoparticles; PDA: polydopamine; NGR: peptide (CYGGRGNG); MSN-DOX-PDA-NGR: polydopamine (PDA)-coated mesoporous sílica nanoparticles (NPs, MSNs) and the PDA coating was functionalized with Asn-Gly-Arg (NGR); PSM: PTX-loaded SLN modified with TOC; CooP: peptide (ACGLSGLGVA)X; NP-PTX: paclitaxel-loading PEG–PLA nanoparticles; CTX: Chlorotoxin; SNALPs: stable nucleic acid lipid particle; NP-TPC: Nanoparticle- 5-(4-carboxyphenyl)-10,15,20-triphenylchlorin; ATWLPPR: H-Ala-Thr-Trp-Leu-Pro-Pro-Arg-OH; IRNPs: IL-13p and RGD conjugated PEG-PCL nanoparticles; SapC-DOPS: Saposin C-dioleoylphosphatidylserine; FePro: Ferumoxides-Protamine Sulfate; VEGF: Vascular Endothelial Growth Factor; NS: Nanoshells (silica core/gold shell nanoparticles); NWs: iron oxide nanoparticles, dubbed “nanoworms” (NWs); CGKRKD: Cys-Gly-Lys-Arg-Lys peptide; KLAKLAK: α-helical amphipathic peptide D; PMLA (P): poly(β-l-malic acid); LLL: H2N-Leu-Leu-Leu-OH; AON: antisense oligonucleotide; Hu: mAb targeting tumor cells (human TfR); Ms: mAb targeting blood–brain tumor barrier endothelium (mouse TfR); LOEt: H2N-Leu-Leu-Leu-NH2, H2N-Leu-ethylester; TfR: transferrin receptor; DOX-np: Doxorubicin-loaded polysorbate 80-coated poly(butyl cyanoacrylate) (PBCA) nanoparticles; Ls-TPT: liposomal topotecan; RTKs: Receptor Tirosina Kinase; VEGFR-2: Vascular Endothelial Growth Factor Receptor- 2; VEGRF-3: Vascular Endothelial Growth Factor Receptor – 3; PDGFR-β: Platelet derived growth factor receptor- β; c-Kit: Stem Cell Factor Receptor; Flt-3: FMS-like tyrosine kinase 3; Raf-1: Serine/threonine-protein kinase; B-Raf: RAF kinase type B gene; B-Raf-mut: RAF kinase type B gene mutated; IL-4R: interleukin 4 receptor; CXCR4: C-X-C chemokine receptor type 4; PI3K/Akt: signaling pathway; MMPs: Matrix Metalloproteinases; CD11b+: Cluster of Differentiation 11b; GBM: Glioblastoma; EphA2: EPH Receptor A2; SPARC: Secreted Protein, Acidic and Rich in Cysteines; gp60: 60-kDa sialoglycoprotein; CA IX: Carbonic anhydrase IX; HIF-1α: Hypoxia-Inducible Factor 1-α; HSPG: Heparan Sulfate Proteoglycan; NRP-1: Neuropilin-1; CD13: Cluster of Differentiation 13; SSTR2: Somatostatin Receptor Type 2; Glut1: Glucose Transporter 1; BBB: Blood–Brain Barrier; MDGI: Mammary-Derived Growth Inhibitor; H-FABP: Heart-Type Fatty Acid Binding Protein; FABP3: Fatty Acid Binding Protein 3; miR-21: microRNA 21; PDCD4: Programmed Cell Death 4; RhoB: Ras Homolog Family Member B; p53: Protein 53 kDa; TGF-β: Transforming growth factor β; IL13Rα2: Interleukin-13 Receptor α2; PtdSer: Phosphatidylserine; CD34: Cluster of Differentiation 34; AC133: Prominin-1; SDF-1: Stromal Cell-Derived Factor 1; 4-HPR: N-(4-Hydroxyphenyl)retinamide; BLI: Bio-layer interferometry; iPDT: Interstitial Photodynamic Therapy; IHC: Immunohistochemistry; H&E: Eosin and Hematoxylin; MRI: Magnetic Resonance Imaging; IF: Immunofluorescence; WB: Western Blotting; PET-CT: Positron Emission Tomography – Computed Tomography; IMC: Isothermal Microcalorimetry.