Polyethylene glycol–polylactic acid nanoparticles modified with cysteine–arginine–glutamic acid–lysine–alanine fibrin-homing peptide for glioblastoma therapy by enhanced retention effect

Abstract

For a nanoparticulate drug-delivery system, crucial challenges in brain-glioblastoma therapy are its poor penetration and retention in the glioblastoma parenchyma. As a prevailing component in the extracellular matrix of many solid tumors, fibrin plays a critical role in the maintenance of glioblastoma morphology and glioblastoma cell differentiation and proliferation. We developed a new drug-delivery system by conjugating polyethylene glycol–polylactic acid nanoparticles (NPs) with cysteine–arginine–glutamic acid–lysine–alanine (CREKA; TNPs), a peptide with special affinity for fibrin, to mediate glioblastoma-homing and prolong NP retention at the tumor site. In vitro binding tests indicated that CREKA significantly enhanced specific binding of NPs with fibrin. In vivo fluorescence imaging of glioblastoma-bearing nude mice, ex vivo brain imaging, and glioblastoma distribution demonstrated that TNPs had higher accumulation and longer retention in the glioblastoma site over unmodified NPs. Furthermore, pharmacodynamic results showed that paclitaxel-loaded TNPs significantly prolonged the median survival time of intracranial U87 glioblastoma-bearing nude mice compared with controls, Taxol, and NPs. These findings suggested that TNPs were able to target the glioblastoma and enhance retention, which is a valuable strategy for tumor therapy.

Encapsulation and Storage of Therapeutic Fibrin-Homing Peptides using Conducting Polymer Nanoparticles for Programmed Release by Electrical Stimulation

“…In order to improve the efficacy of CREKA-based diagnoses and therapies, most research has focused on loading this peptide in active targeting nanoparticles (NPs). For example, CREKA has been conjugated with polymer NPs − [e.g., poly­(ethylene glycol) (PEG), PEG-poly­(lactic acid), and polyamidoamine dendrimers], polymer–metal and polymer–metal oxide hybrid NPs , [e.g., Au-PEG, Fe 2 O 3 –PEG, and Fe 3 O 4 -poly­(lactic- co -glycolic acid)], and inorganic NPs ,− (e.g., Fe 2 O 3 and mesoporous silica) for targeted imaging of tumor cells and cancer therapies. Furthermore, this pentapeptide has been encapsulated in liposomes for antimetastasis therapies against breast cancer .…”

“…In this work we are not focused on the therapeutic applications of CREKA, which have been extensively discussed, − ,, but on developing an electroactive bioplatform for storage and on-demand peptide release by electrical stimulation. For this purpose, PEDOT NPs obtained by emulsion polymerization were loaded in situ with CREKA for electro-stimulated release.…”

“…29 In the absence of thrombin, PEDOT/CREKA induced a stepwise linear growth of fibrin particles. 29 In this work we are not focused on the therapeutic applications of CREKA, which have been extensively discussed, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]28,29 but on developing an electroactive bioplatform for storage and on-demand peptide release by electrical stimulation. For this purpose, PEDOT NPs obtained by emulsion polymerization were loaded in situ with CREKA for electro-stimulated release.…”

Improved anti-glioblastoma efficacy by IL-13Rα2 mediated copolymer nanoparticles loaded with paclitaxel

“…The intracranial tumor xenograft model was established by inoculation of C6 cells (5.0 × 10 5 cells suspended in 5 μL PBS) into the the right striatum (1.8 mm lateral to the bregma and 3 mm of depth) of male Balb/c mice. The release of Dir from NPs is very low, indicating that Dir could be accurate fluorescence probes for NP behavior in vivo , and the fluorescence signals detected in organs well represented the distribution of the NPs 40 . After cultured for 14 days, the glioma-bearing mice were injected with Dir-loaded NP and Pep-NP at the dose of 0.8 mg/kg Dir, the concentration of Dir was measured by fluorescent spectrophotometer.…”

Local Delivery and Glioblastoma: Why Not Combining Sustained Release and Targeting?

“…The significant presence of fibrin-FN complexes is found in many invasive tumors, including GBM ( 163 ). These complexes play an important role in survival, the proliferation and invasion of cancer cells, making it another attractive target for the treatment of GBM ( 164 ). Wang et al ( 83 ) functionalized PLGA nanoparticle surface with the Pep-1 and CREKA peptides (Pep-1/CREKA-NP).…”