Abstract
Malignant brain glioma is the most lethal and aggressive type of cancer. Surgery and radiotherapy cannot eliminate all glioma stem cells (GSCs) and blood–brain barrier (BBB) restricts the movement of antitumor drugs from blood to brain, thus leading to the poor prognosis with high recurrence rate. In the present study, the targeting conjugates of cholesterol polyethylene glycol polyethylenimine (CHOL-PEG2000-PEI) and D-a-tocopheryl polyethylene glycol 1000 succinate vapreotide (TPGS1000-VAP) were newly synthesized for transporting drugs across the BBB and targeting glioma cells and GSCs. The multifunctional targeting vinorelbine plus tetrandrine liposomes were constructed by modifying the targeting conjugates. The studies were undertaken on BBB model, glioma cells, GSCs, and glioma-bearing mice. In vitro results showed that multifunctional targeting drugs-loaded liposomes with suitable physicochemical property could enhance the transport drugs across the BBB, increase the intracellular uptake, inhibit glioma cells and GSCs, penetrate and destruct the GSCs spheroids, and induce apoptosis via activating related apoptotic proteins. In vivo results demonstrated that multifunctional targeting drugs-loaded liposomes could significantly accumulate into brain tumor location, show the specificity to tumor sites, and result in a robust overall antitumor efficacy in glioma-bearing mice. These data suggested that the multifunctional targeting vinorelbine plus tetrandrine liposomes could offer a promising strategy for treating brain glioma.
Highlights
Malignant glioma is a type of tumor that starts in brain or spine and accounts for 80% of all brain tumors
The therapeutic failure of the combination treatment is related to the following factors: 1) the blood‐brain barrier (BBB) provides significant barrier to the effective chemotherapy [3]; 2) the multidrug resistance (MDR) results in incomplete therapeutic response and unsuccessful tumor chemotherapy [4]; 3) the existence of glioma stem cells (GSCs) is responsible for invasion, recurrence and metastasis of brain glioma [5]
To synthesize CHOL‐PEG2000‐PEI conjugate, PEI was conjugated to distal end of the CHOL‐PEG2000‐NHS by a nucleophilic substitution reaction
Summary
Malignant glioma is a type of tumor that starts in brain or spine and accounts for 80% of all brain tumors. A combined approach using chemotherapy, surgery and radiotherapy is applied for the treatment of brain glioma. The median patient survival is only 1–2 years and no significant differences in overall survival are found after the conventional treatment [2]. The therapeutic failure of the combination treatment is related to the following factors: 1) the blood‐brain barrier (BBB) provides significant barrier to the effective chemotherapy [3]; 2) the multidrug resistance (MDR) results in incomplete therapeutic response and unsuccessful tumor chemotherapy [4]; 3) the existence of glioma stem cells (GSCs) is responsible for invasion, recurrence and metastasis of brain glioma [5]. It is crucial to find an approach to transport drugs effectively across the BBB, inhibit the MDR and eliminate all the glioma cells and GSCs
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