Table 1. . Antiangiogenic therapies that have been investigated for the treatment of glioblastoma.
| Antiangiogenic factor | Combined with | Biomaterials | In vivo model | Outcome | Ref. |
|---|---|---|---|---|---|
| Small-molecule drugs | |||||
| Minocycline (local) | Radiotherapy or TMZ (chemotherapy, systemic) | pCPP:SA | Rat intracranial 9L GBM model | Minocycline delivered locally potentiates the effects of both radiotherapy and oral TMZ in increasing median survival | [40] |
| Minocycline (local) | BCNU (chemotherapy, systemic) | pCPP:SA | Rat intracranial 9L GBM model | The combination of intracranial minocycline and systemic BCNU extended median survival compared with systemic BCNU alone | [41] |
| Minocycline (local or systemic) |
BCNU (chemotherapy, systemic) | EVAc disk | Rat intracranial C6 GBM model | Treatment with a combination of minocycline delivered locally in a controlled-release polymer and systemic BCNU 5 days after tumor implantation resulted in an extension of median survival time compared with BCNU alone | [42] |
| Docetaxel (systemic) | PEG-PCL nanoparticles with IL-13 peptide and RGD targeting agents (IRNPs) | Mouse intracranial C6 GBM model | Docetaxel-IRNPs displayed best antitumor effect, with a median survival time of 35 days, which was significantly longer than that seen with mono-modified and unmodified nanoparticles | [43] | |
| Sorafenib (local) |
LNCs made from Lipoid S75-3 (soybean lecithin with 70% phosphatidylcholine and 10% phosphatidylethanolamine) and Kolliphor HS15 (mixture of free PEG 660 and PEG 660 hydroxystearate) | Mouse intracranial U87MG GBM model | SFN-LNCs or free SFN decreased the proportion of proliferating cells in the tumor relative to control groups. SFN-LNCs were more effective than free SFN in inducing early tumor vascular normalization | [36] | |
| Nelfinavir or amprenavir (systemic) | Oral with feed | Mouse subcutaneous U87MG Matrigel plugs GBM model (nelfinavir only) |
In vitro: nelfinavir and amprenavir downregulate VEGF and HIF-1 expression In vivo: nelfinavir decreased angiogenesis |
[44] | |
| Combretastatin (local) | BIC (chemotherapy, local) | PLGA nanofibrous membrane | Mouse intracranial C6 GBM model | BICC/PLGA nanofibrous membranes (i.e. BIC combined with combretastatin) decreased malignancy, retarded tumor growth and prolonged survival compared with BIC/PLGA nanofibrous membranes | [45] |
| Nucleic acids | |||||
| Plasmid-encoding secreted HGFK1 gene (pHGFK1) (local) | Radiotherapy (IR) | H1, a cationic co-polymer consisting of low-molecular-weight (600 Da) PEI linked by β-cyclodextrin and conjugated with folic acid Form H1/pHGFK1 nanoparticles (peritumoural injection) |
Mouse subcutaneous U87MG GBM model Mouse intracranial U118 cell model |
H1/pHGFK1 nanoparticles significantly inhibited tumor growth and prolonged survival in tumor-bearing mice and enhanced the antitumoral efficacy of IR | [46] |
| Plasmid-encoding non-collagenous C-terminal globular NC1 domain of type VIII collagen a1 chain, Vastatin (local) | TMZ (chemotherapy, systemic) | PEI600-CyD-Folate (H1), a cationic co-polymer consisting of low-molecular-weight (600 Da) PEI linked by β-cyclodextrin and conjugated with folic acid | Mouse intracranial U8MG or U87-ATR (chemoresistant) GBM model | Enhancing Vastatin expression by intracerebral injection of H1-Vastatin significantly prolonged animal survival, comparable to the effect of endostatin, the most studied endogenous antiangiogenic polypeptide. Synergistic effect in extending survival was detected when H1-Vastatin was administered with TMZ in GBM chemoresistant murine models |
[47] |
| RNAi plasmid targeting MMP-2 (siRNA MMP-2) (local) | PTX (local) | PEI nonviral vector PLGA nanofibrous membrane |
Mouse intracranial U87MG GBM model | PTX/siRNA dual implant significantly enhanced tumor growth inhibition relative to PTX implant only | [48] |
| Plasmid expressing interfering RNA targeting VEGF (shVEGF) (systemic) | Dox (chemotherapy, systemic) |
dtACPP-modified nanoparticles | Mouse U87MG intracranial GBM model | Utilizing dtACPP-modified nanoparticles to co-deliver plasmid expressing interfering RNA targeting VEGF (shVEGF) and Dox (designated dtACPPD/shVEGFDOX) resulted in effective shutdown of blood vessels and cell apoptosis within the tumor | [49] |
| Soluble VEGFR (sFlt-1) and an angiostatin–endostatin fusion gene (statin-AE) with Sleeping Beauty transposon (local) | PEI nonviral vector | Mouse subcutaneous U373 or U87MG GBM model Mouse intracranial U87MG GBM model |
Co-injection of transgenes sFlt-1 and statin-AE showed marked antitumor activity, as demonstrated by reduction of tumor vessel density, inhibition or termination of glioma growth and increase in animal survival Sustained tumor regression of intracranial gliomas was achieved only when statin-AE and sFlt-1 transposons were co-administered with SB-transposase-encoding DNA to facilitate long-term expression |
[50] | |
| Peptides | |||||
| PF-4/CTF, a 23 amino acid CTF of PF-4 (local) | PLGA microspheres | Mouse subcutaneous U87MG GBM model Mouse intracranial U87MG GBM model |
A single injection of microspheres containing PF-4/CTF resulted in reduction in tumor volume, with a significant decrease in angiogenesis and an increase in apoptosis | [51] | |
| Fc-endostatin (local implantation or CED or systemic injection) | TMZ (chemotherapy, systemic) | pCPP:SA wafer | Rat intracranial 9L GBM model | Systemically or locally delivered mFc-endostatin prolonged the survival of rats implanted with intracranial 9L gliosarcoma. This benefit was further enhanced when mFc-endostatin was combined with the oral chemotherapeutic agent TMZ | [52] |
| Bevacizumab (systemic) | PLGA nanoparticles | Mouse intracranial U87MG GBM model | Bevacizumab-loaded PLGA nanoparticles were able to increase the penetration and residence time of bevacizumab in the brain and demonstrated a reduction in tumor growth accompanied by a higher antiangiogenic effect compared with free bevacizumab | [53] | |
| Biomaterials as standalone therapeutics | |||||
| Carbon nanoparticles | Nanoparticles of carbon allotropes (UDD and MW/RF) | In ovo: chorioallantoic membrane chicken embryo U87MG model | UDD and MW/RF nanoparticles reduced tumor mass and volume and inhibited new blood vessel development in cultured GBM tumors | [54] | |
BCNU: Bis-chloroethylnitrosourea; BIC: Bis-chloroethylnitrosourea, irinotecan and cisplatin; BICC: Bis-chloroethylnitrosourea, irinotecan, cisplatin and combretastatin; CED: Convection-enhanced delivery; pCPP:SA: Poly(1,3-bis-[p-carboxyphenoxy propane]-co-[sebacic anhydride]); CTF: C-terminal fragment; Dox: Doxorubicin; dtACPP: Dual-triggered nanoparticle system decorated with an activatable cell-penetrating peptide; GBM: Glioblastoma multiforme; EVAc: Ethylene vinyl acetate copolymer; IRNPs: IL-13 RGD nanoparticles; IR: Ionizing radiation; LNC: Lipid nanocapsule; MW/RF: Microwave/radiofrequency; pCPP:SA: Polyanhydride poly[bis(p-carboxyphenoxy)propane-sebacic acid]; PEG: Polyethylene glycol; PEG-PCL: Polyethylene glycol–poly(ε-caprolactone); PEI: Polyethylenimine; PLGA: Poly[(d,l)-lactide-co-glycolide]; PTX: Paclitaxel; RGD: Arg-Gly-Asp; SFN: Sorafenib; TMZ: Temozolomide; UDD: Ultradispersed detonation diamond.