The synergistic effect of chlorotoxin-mApoE in boosting drug-loaded liposomes across the BBB

Formicola, Beatrice; Magro, Roberta Dal; Montefusco-Pereira, Carlos Victor; Lehr, Claus‐Michael; Koch, Marcus; Russo, Laura; Grasso, Gianvito; Deriu, Marco Agostino; Danani, Andrea; Bourdoulous, Sandrine

doi:10.1186/s12951-019-0546-3

Cited by 24 publications

(21 citation statements)

References 25 publications

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“…The ability of human primary glioblastoma cell line (U87-MG), in comparison with NHA, to exchange Mf-LIP via TnTs has been investigated. Mf-LIP characterization has shown that the different batches herein prepared were highly reproducible and stable over time, with the yield of the reactions comparable with those of previously reported ones (Re et al, 2010(Re et al, , 2011Formicola et al, 2019).…”

Section: Discussionsupporting

confidence: 79%

“…Among the different ways that cells used to exchange non-secretable messages, TnTs and TmTs are involved in the re-growth of GBM after surgery and in conferring resistance to radiotherapy and chemotherapy (Moschoi et al, 2016;Weil et al, 2017). Starting from our expertise in the design of nanoparticles, we synthesized and characterized LIP carry doxorubicin, as an anti-cancer drug model, and dually functionalized with mApoE and with ClTx, as GBM targeting ligands (DeBin et al, 1993;Maletínská et al, 2000;Lyons et al, 2002;Ojeda et al, 2016;Formicola et al, 2019). The ability of human primary glioblastoma cell line (U87-MG), in comparison with NHA, to exchange Mf-LIP via TnTs has been investigated.…”

Section: Discussionmentioning

confidence: 99%

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Differential Exchange of Multifunctional Liposomes Between Glioblastoma Cells and Healthy Astrocytes via Tunneling Nanotubes

Formicola

D’Aloia

Magro

et al. 2019

Front. Bioeng. Biotechnol.

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Despite advances in cancer therapies, nanomedicine approaches including the treatment of glioblastoma (GBM), the most common, aggressive brain tumor, remains inefficient. These failures are likely attributable to the complex and not yet completely known biology of this tumor, which is responsible for its strong invasiveness, high degree of metastasis, high proliferation potential, and resistance to radiation and chemotherapy. The intimate connection through which the cells communicate between them plays an important role in these biological processes. In this scenario, tunneling nanotubes (TnTs) are recently gaining importance as a key feature in tumor progression and in particular in the re-growth of GBM after surgery. In this context, we firstly identified structural differences of TnTs formed by U87-MG cells, as model of GBM cells, in comparison with those formed by normal human astrocytes (NHA), used as a model of healthy cells. Successively, we have studied the possibility to exploit U87-MG TnTs as drug-delivery channels in cancer therapy, using liposomes composed of cholesterol/sphingomyelin and surface functionalized with mApoE and chlorotoxin peptides (Mf-LIP) as nanovehicle model. The results showed that U87-MG cells formed almost exclusively thick and long protrusions, whereas NHA formed more thin and short TnTs. Considering that thick TnTs are more efficient in transport of vesicles and organelles, we showed that fluorescent-labeled Mf-LIP can be transported via TnTs between U87-MG cells and with less extent through the protrusions formed by NHA cells. Our results demonstrate that nanotubes are potentially useful as drug-delivery channels for cancer therapy, facilitating the intercellular redistribution of this drug in close and far away cells, thus reaching isolated tumor niches that are hardly targeted by simple drug diffusion in the brain parenchyma. Moreover, the differences identified in TnTs formed by GBM and NHA cells can be exploited to increase treatment precision and specificity.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Differential Exchange of Multifunctional Liposomes Between Glioblastoma Cells and Healthy Astrocytes via Tunneling Nanotubes

Formicola

D’Aloia

Magro

et al. 2019

Front. Bioeng. Biotechnol.

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“…We anticipate that the incorporation of the insights and lessons learned from this post-hoc analysis in the further clinical evaluation and development of OT101 will help improve the potential for patient benefit. While a CED system has been used to deliver OT101 in clinical trials to date, it may also be possible in the future to administer OT101 without a neurosurgical intervention as a payload in a nanoformulation that can cross the blood-brain-barrier (BBB) via active transport mechanisms employing receptor-mediated or adsorption-mediated endocytosis, including but not limited to poly(lactic-co-glycolic acid) (PLGA)-based polymeric nanoparticles and targeted nanoliposomes [39,40]. It may also be possible to achieve therapeutic CNS delivery of OT101 by using clinically available methods of transient and repeated BBB disruption, such as the MRI-guided focused ultrasound-mediated drug delivery platform [41] or low intensity pulsed ultrasound (LIPU) using a cranial ultrasound device that can be activated prior to drug administration at [42,43].…”

Section: Discussionmentioning

confidence: 99%

Recurrent or Refractory High-Grade Gliomas Treated by Convection-Enhanced Delivery of a TGFβ2-Targeting RNA Therapeutic: A Post-Hoc Analysis with Long-Term Follow-Up

Uckun¹,

Qazi

Hwang³

et al. 2019

Cancers

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Background. OT101 is a first-in-class RNA therapeutic designed to abrogate the immunosuppressive actions of transforming growth factor beta 2 (TGFβ2). Here, we report our post-hoc analysis of the single-agent activity of OT101 in adult patients with recurrent and/or refractory (R/R) high-grade gliomas. Methods. In a Phase 2 clinical trial (ClinicalTrials.gov, NCT00431561), OT101 was administered to 89 R/R high-grade glioma (HGG) (anaplastic astrocytoma/AA: 27; glioblastoma multiforme/GBM: 62) patients with an intratumoral catheter using a convection enhanced delivery (CED) system. Seventy-seven patients (efficacy population; GBM: 51; AA: 26) received at least the intended minimum number of four OT101 treatment cycles. Response determinations were based on central review of magnetic resonance imaging (MRI) scans according to the McDonald criteria. Standard statistical methods were applied for the analysis of data. Findings. Nineteen patients had a complete response (CR) or partial response (PR) following a slow but robust size reduction of their target lesions (median time for 90% reduction of the baseline tumor volume = 11.7 months, range: 4.9-57.7 months). The mean log reduction of the tumor volume was 2.2 ± 0.4 (median = 1.4: range: 0.4-4.5) logs. In addition, seven patients had a stable disease (SD) lasting ≥6 months. For the combined group of 26 AA/GBM patients with favorable responses, the median progression-free survival (PFS) of 1109 days and overall survival (OS) of 1280 days were significantly better than the median PFS (p < 0.00001) and OS (p < 0.00001) of the non-responders among the 89 patients or the 77-patient efficacy population. Conclusion. Intratumorally administered OT101 exhibits clinically meaningful single-agent activity and induces durable CR/PR/SD in R/R HGG patients.

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“…Once bound to the receptors on glioma cell surface, the peptide can be internalized into cells. These unique biological properties of CTX make it a potential targeting agent for glioma diagnosis and therapy [32][33][34]. Perceiving this, the feasibility of using radionuclide 131 I and fluorescent molecule (indocyanine green) labeled CTX molecules for glioma imaging and treatment has been investigated in clinical trials [35,36].…”

Section: Introductionmentioning

confidence: 99%

Polyethylenimine-based theranostic nanoplatform for glioma-targeting single-photon emission computed tomography imaging and anticancer drug delivery

et al. 2020

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Background Glioma is the deadliest brain cancer in adults because the blood–brain-barrier (BBB) prevents the vast majority of therapeutic drugs from entering into the central nervous system. The development of BBB-penetrating drug delivery systems for glioma therapy still remains a great challenge. In this study, we aimed to design and develop a theranostic nanocomplex with enhanced BBB penetrability and tumor-targeting efficiency for glioma single-photon emission computed tomography (SPECT) imaging and anticancer drug delivery. Results This multifunctional nanocomplex was manufactured using branched polyethylenimine (PEI) as a template to sequentially conjugate with methoxypolyethylene glycol (mPEG), glioma-targeting peptide chlorotoxin (CTX), and diethylenetriaminepentaacetic acid (DTPA) for 99mTc radiolabeling on the surface of PEI. After the acetylation of the remaining PEI surface amines using acetic anhydride (Ac2O), the CTX-modified PEI (mPEI-CTX) was utilized as a carrier to load chemotherapeutic drug doxorubicin (DOX) in its interior cavity. The formed mPEI-CTX/DOX complex had excellent water dispersibility and released DOX in a sustainable and pH-dependent manner; furthermore, it showed targeting specificity and therapeutic effect of DOX toward glioma cells in vitro and in vivo (a subcutaneous tumor mouse model). Owing to the unique biological properties of CTX, the mPEI-CTX/DOX complex was able to cross the BBB and accumulate at the tumor site in an orthotopic rat glioma model. In addition, after efficient radiolabeling of PEI with 99mTc via DTPA, the 99mTc-labeled complex could help to visualize the drug accumulation in tumors of glioma-bearing mice and the drug delivery into the brains of rats through SPECT imaging. Conclusions These results indicate the potential of the developed PEI-based nanocomplex in facilitating glioma-targeting SPECT imaging and chemotherapy.

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The synergistic effect of chlorotoxin-mApoE in boosting drug-loaded liposomes across the BBB

Cited by 24 publications

References 25 publications

Differential Exchange of Multifunctional Liposomes Between Glioblastoma Cells and Healthy Astrocytes via Tunneling Nanotubes

Differential Exchange of Multifunctional Liposomes Between Glioblastoma Cells and Healthy Astrocytes via Tunneling Nanotubes

Recurrent or Refractory High-Grade Gliomas Treated by Convection-Enhanced Delivery of a TGFβ2-Targeting RNA Therapeutic: A Post-Hoc Analysis with Long-Term Follow-Up

Polyethylenimine-based theranostic nanoplatform for glioma-targeting single-photon emission computed tomography imaging and anticancer drug delivery

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