Anticancer drugs loaded into tumor- and vasculature-targeted nanocarriers (NC) can reduce side-effects and improve therapeutic efficacy in pre-clinical studies. However, poorly perfused and dysfunctional tumor vessels and lymphatics limit... more
Anticancer drugs loaded into tumor- and vasculature-targeted nanocarriers (NC) can reduce side-effects and improve therapeutic efficacy in pre-clinical studies. However, poorly perfused and dysfunctional tumor vessels and lymphatics limit the transport of the payload into the parenchyma of solid tumors. The use of NC decorated with tumor-penetrating peptides (TPPs) might enhance tumor penetration and antitumor effects. A previously characterized neuroblastoma (NB)-targeting peptide ligand was here modified (now referred as TPP-NB) by adding a consensus motif as a mediator of cell, vascular and tissue penetration via neuropilin-1 (NRP-1) receptor recognition. NPR-1 expression was validated by FACS analysis in NB cell lines and by IHC staining in tumor cells and tumor stroma from NB-bearing mice. Recombinant NRP-1 was used to validate TPP-NB specificity. In vitro and in vivo cell association and internalization of TPP-NB, either free or coupled to Liposomes (L) were tested by FACS and confocal microscopy. Vascular permeability assay after treatment with TPP-NB-targeted, doxorubicin-loaded Liposomes (TPP-NB-L[DXR]) was performed evaluating the in vivo accumulation of Evans Blue dye within the tumor mass. Therapeutic experiments with TPP-NB-L[DXR] were performed in mice orthotopically injected with human NB cells. NRP-1 expression is validated in a panel of NB cells and in tumors from NB-bearing mice. Differently from the original peptide and some control ones, TPP-NB is able to recognize recombinant NRP-1. The addition of the NRP-1-recognizing sequence to the original peptide significantly increases its NB cellular association in vitro. Interestingly, the results seem to indicate that the enhanced capability by TPP-NB in binding NB cells is related to the combination of the NRP-1-recognizing and the original sequence. Importantly, TPP-NB coupled at the external surfaces of L[DXR] significantly increases their cellular association on NB cells in vitro. Competitive binding assay reveals that binding of TPP-NB is specific and can be inhibited by an excess of the unlabeled free peptide. The localization and the cellular distribution of L evaluated by confocal microscopy in vitro and in mouse models of NB, confirm the binding specificity, showing an increased selective internalization of TPP-NB-L-FITC compared to that obtained with either untargeted L or L decorated with the scrambled peptide. Moreover, TPP-NB-L[DXR] further increases the vascular permeability into the NB tumor mass, but not in non-tumor tissues. The therapeutic efficacy of TPP-NB-L[DXR] has been investigating in terms of overall survival. On running results indicate that the novel NC exerts an increased anti-NB effect compared to DXR-loaded L decorated with the original peptide. Our findings demonstrate that the achieved penetrating features by a NB-targeting peptide might increase liposomal drug binding, homing and antitumor efficacy. Citation Format: Fabio Pastorino, Chiara Brignole, Laura Emionite, Silvia Bruno, Flavio Curnis, Daniela Di Paolo, Patrizia Perri, Alessandro Gori, Renato Longhi, Michele Cilli, Angelo Corti, Mirco Ponzoni. Tumor-penetrating peptide-coated nanoparticles as a novel strategy for the targeted therapy of neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5130. doi:10.1158/1538-7445.AM2017-5130
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Research Interests: Genetics, Biology, Transcription Factors, Medicine, Multidisciplinary, and 14 moreGene Silencing, Cell line, Humans, Neural Crest, Childhood Cancer, Transcription Factor, PLoS one, Neuroblastoma, Gene Targeting, Anaplastic Lymphoma Kinase (ALK), Molecular Interactions, Receptor Tyrosine Kinase, Protein tyrosine kinases, and In Vitro Techniques
Despite improvements in therapies and screening strategies, lung cancer prognosis still remains dismal, especially for metastatic tumors. Cancer stem cells (CSCs) are endowed with properties such as chemoresistance, dissemination, and... more
Despite improvements in therapies and screening strategies, lung cancer prognosis still remains dismal, especially for metastatic tumors. Cancer stem cells (CSCs) are endowed with properties such as chemoresistance, dissemination, and stem-like features, that make them one of the main causes of the poor survival rate of lung cancer patients. MicroRNAs (miRNAs), small molecules regulating gene expression, have a role in lung cancer development and progression. In particular, mir-486-5p is an onco-suppressor miRNA found to be down-modulated in the tumor tissue of lung cancer patients. In this study, we investigate the role of this miRNA in CD133+ lung CSCs and evaluate the therapeutic efficacy of coated cationic lipid-nanoparticles entrapping the miR-486-5p miRNA mimic (CCL-486) using lung cancer patient-derived xenograft (PDX) models. In vitro, miR-486-5p overexpression impaired the PI3K/Akt pathway and decreased lung cancer cell viability. Moreover, miR-486-5p overexpression induced...
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Targeted delivery of anticancer drugs with nanocarriers can reduce side effects and ameliorate therapeutic efficacy. However, poorly perfused and dysfunctional tumor vessels limit the transport of the payload into solid tumors. The use of... more
Targeted delivery of anticancer drugs with nanocarriers can reduce side effects and ameliorate therapeutic efficacy. However, poorly perfused and dysfunctional tumor vessels limit the transport of the payload into solid tumors. The use of tumor-penetrating nanocarriers might enhance tumor uptake and antitumor effects. A peptide containing a tissue-penetrating (TP) consensus motif, capable of recognizing neuropilin-1, is here fused to a neuroblastoma-targeting peptide (pep) previously developed. Neuroblastoma cell lines and cells derived from both xenografts and high-risk neuroblastoma patients show overexpression of neuropilin-1. In vitro studies reveal that TP-pep binds cell lines and cells derived from neuroblastoma patients more efficiently than pep. TP-pep, after coupling to doxorubicin-containing stealth liposomes (TP-pep-SL[doxorubicin]), enhances their uptake by cells and cytotoxic effects in vitro, while increasing tumor-binding capability and homing in vivo. TP-pep-SL[doxor...
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Macrophages, cells belonging to the innate immune system, present a high plasticity grade, being able to change their phenotype in response to environmental stimuli. They play central roles during development, homeostatic tissue... more
Macrophages, cells belonging to the innate immune system, present a high plasticity grade, being able to change their phenotype in response to environmental stimuli. They play central roles during development, homeostatic tissue processes, tissue repair, and immunity. Furthermore, it is recognized that macrophages are involved in chronic inflammation and that they play central roles in inflammatory diseases and cancer. Due to their large involvement in the pathogenesis of several types of human diseases, macrophages are considered to be relevant therapeutic targets. Nanotechnology-based systems have attracted a lot of attention in this field, gaining a pivotal role as useful moieties to target macrophages in diseased tissues. Among the different approaches that can target macrophages, the most radical is represented by their depletion, commonly obtained by means of clodronate-containing liposomal formulations and/or depleting antibodies. These strategies have produced encouraging re...
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Research Interests: Technology, Biomarkers, Biological Sciences, Adenosine, Liver Cirrhosis, and 13 moreMice, Animals, Male, Hepatic Stellate Cells, Myofibroblasts, Histones, Carbon Tetrachloride, Disease Progression, Molecular Targeted Therapy, Gene Expression Regulation, Gene expression profiling, Medical and Health Sciences, and Collagen type I
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Neuronal pentraxins (NPTX) and their corresponding receptors (NPTXR) have been studied as synapse-associated proteins in the nervous system, but their role in cancer is largely unknown. By applying a multidisciplinary, high-throughput... more
Neuronal pentraxins (NPTX) and their corresponding receptors (NPTXR) have been studied as synapse-associated proteins in the nervous system, but their role in cancer is largely unknown. By applying a multidisciplinary, high-throughput proteomic approach, we have recently identified a peptide ligand motif for targeted drug delivery to neuroblastoma. Here we report the sequence similarity between this peptide and a conserved portion of the pentraxin domain that is involved in the homo- and hetero-oligomerization of NPTX2 and NPTXR. We show that, in comparison to normal tissues, NPTX2 and NPTXR are overexpressed in vivo in mouse models, as well as in human Schwannian stroma-poor, stage IV neuroblastoma. Both proteins are concentrated in the vicinity of tumor blood vessels, with NPTXR also present on neuroblastic tumor cells. In vivo targeting of NPTX2 and NPTXR with the selected peptide or with specific antibodies reduces tumor burden in orthotopic mouse models of human neuroblastoma. ...
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Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a promising... more
Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a promising therapeutic target. The ALK-inhibitor crizotinib has a limited activity against the various ALK mutations identified in NB patients. We tested: the activity of the novel ALK-inhibitor X-396 administered alone or in combination with Targeted Liposomes carrying ALK-siRNAs (TL[ALK-siRNA]) that are active irrespective of ALK gene mutational status; the pharmacokinetic profiles and the biodistribution of X-396; the efficacy of X-396 versus crizotinib treatment in NB xenografts; whether the combination of X-396 with the TL[ALK-siRNA] could promote long-term survival in NB mouse models. X-396 revealed good bioavailability, moderate half-life, high mean plasma and tumor concentrations. X-396 was more effective than crizotinib in inhibiting in vitro cell prolif...
Research Interests: Nanoparticles, Signal Transduction, RNA interference, Humans, Mutation, and 15 moreFemale, Animals, Male, Liposomes, Neuroblastoma, Shell Half-Life, Transfection, Cell Proliferation, Biological Availability, Cell Survival, Antineoplastic Agents, Molecular Targeted Therapy, Protein Kinase Inhibitors, RNAi Therapeutics, and Combined Modality Therapy
Selective tumor targeting is expected to enhance drug delivery and to decrease toxicity, resulting in an improved therapeutic index. We have recently identified the HSYWLRS peptide sequence as a specific ligand for aggressive... more
Selective tumor targeting is expected to enhance drug delivery and to decrease toxicity, resulting in an improved therapeutic index. We have recently identified the HSYWLRS peptide sequence as a specific ligand for aggressive neuroblastoma, a childhood tumor mostly refractory to current therapies. Here we validated the specific binding of HSYWLRS to neuroblastoma cell suspensions obtained either from cell lines, animal models, or Schwannian-stroma poor, stage IV neuroblastoma patients. Binding of the biotinylated peptide and of HSYWLRS-functionalized fluorescent quantum dots or liposomal nanoparticles was dose-dependent and inhibited by an excess of free peptide. In animal models obtained by the orthotopic implant of either MYCN-amplified or MYCN single copy human neuroblastoma cell lines, treatment with HSYWLRS-targeted, doxorubicin-loaded Stealth Liposomes increased tumor vascular permeability and perfusion, enhancing tumor penetration of the drug. This formulation proved to exert a potent antitumor efficacy, as evaluated by bioluminescence imaging and micro-PET, leading to (i) delay of tumor growth paralleled by decreased tumor glucose consumption, and (ii) abrogation of metastatic spreading, accompanied by absence of systemic toxicity and significant increase in the animal life span. Our findings are functional to the design of targeted nanocarriers with potentiated therapeutic efficacy towards the clinical translation.
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Neuroblastoma is a childhood cancer with poor long-term prognosis in advanced stages. A major aim in neuroblastoma therapy is to develop targeted drug delivery systems to ameliorate drug therapeutic index and efficacy. In this study, a... more
Neuroblastoma is a childhood cancer with poor long-term prognosis in advanced stages. A major aim in neuroblastoma therapy is to develop targeted drug delivery systems to ameliorate drug therapeutic index and efficacy. In this study, a novel bortezomib (BTZ) liposomal formulation was set-up and characterized. Since BTZ is freely permeable across the lipidic bilayer, an amino-lactose (LM) was synthesized as complexing agent to entrap BTZ inside the internal aqueous compartment of stealth liposomes. High encapsulation efficiency was achieved by a loading method based on the formation of boronic esters between the boronic acid moiety of BTZ and the hydroxyl groups of LM. Next, NGR peptides were linked to the liposome surface as a targeting-ligand for the tumor endothelial cell marker, aminopeptidase N. Liposomes were characterized for size, Z-potential, polydispersity index, drug content, and release. Lyophilization in the presence of cryoprotectants (trehalose, sucrose) was also examined in terms of particle size changes and drug leakage. BTZ was successfully loaded into non-targeted (SL[LM-BTZ]) and targeted (NGR-SL[LM-BTZ]) liposomes with an entrapment efficiency of about 68% and 57%, respectively. These nanoparticles were suitable for intravenous administration, presenting an average diameter of 170nm and narrow polydispersity. Therefore, orthotopic NB-bearing mice were treated with 1.0 or 1.5mg/kg of BTZ, either in free form or encapsulated into liposomes. BTZ loaded liposomes showed a significant reduction of drug systemic adverse effects with respect to free drug, even at the highest dose tested. Moreover, mice treated with 1.5mg/kg of NGR-SL[LM-BTZ] lived statistically longer than untreated mice (P=0.0018) and SL[LM-BTZ]-treated mice (P=0.0256). Our results demonstrate that the novel vascular targeted BTZ formulation is endowed with high therapeutic index and low toxicity, providing a new tool for future applications in neuroblastoma clinical studies.
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ABSTRACT Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a... more
ABSTRACT Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a promising therapeutic target. The ALK-inhibitor crizotinib has a limited activity against the various ALK mutations identified in NB patients. We tested: the activity of the novel ALK-inhibitor X-396 administered alone or in combination with Targeted Liposomes carrying ALK-siRNAs (TL[ALK-siRNA]) that are active irrespective of ALK gene mutational status; the pharmacokinetic profiles and the biodistribution of X-396; the efficacy of X-396 versus crizotinib treatment in NB xenografts; whether the combination of X-396 with the TL[ALK-siRNA] could promote long-term survival in NB mouse models. X-396 revealed good bioavailability, moderate half-life, high mean plasma and tumor concentrations. X-396 was more effective than crizotinib in inhibiting in vitro cell proliferation of NB cells and in reducing tumor volume in subcutaneous NB models in a dose-dependent manner. In orthotopic NB xenografts, X-396 significantly increased life span independently of the ALK mutation status. In combination studies, all effects were significantly improved in the mice treated with TL[ALK-siRNA] and X-396 compared to mice receiving the single agents. Our findings provide a rational basis to design innovative molecular-based treatment combinations for clinical application in ALK-driven NB tumors.
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Disseminated neuroectoderma-derived tumors, mainly neuroblastoma in childhood and melanoma in the adulthood, are refractory to most current therapeutic regimens and hence the prognosis remains very poor. Preclinical research studies have... more
Disseminated neuroectoderma-derived tumors, mainly neuroblastoma in childhood and melanoma in the adulthood, are refractory to most current therapeutic regimens and hence the prognosis remains very poor. Preclinical research studies have indicated several agents that show promising therapeutic potential for these neoplasms. However, there appears to be a limitation to their in vivo applicability, mainly due to unfavorable pharmacokinetic properties that lead to insufficient drug delivery to the tumor or metastatic sites or to high systemic or organ-specific toxicity. In this scenario, the focus is on targeted cancer therapy. Encapsulating anticancer drugs in liposomes enables targeted drug delivery to tumor tissue and prevents damage to the normal surrounding tissue. Indeed, sterically stabilized liposomes have been shown to enhance the selective localization of entrapped drugs to solid tumors, with improvements in therapeutic indices. The identification of tumor-associated antigens...
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Neuroblastoma (NB), the most common and deadly extracranial solid tumour of childhood, represents a challenging in paediatric oncology. Soluble tumour necrosis factor (TNF)-related apoptosis-inducing ligand (sTRAIL) is a cancer... more
Neuroblastoma (NB), the most common and deadly extracranial solid tumour of childhood, represents a challenging in paediatric oncology. Soluble tumour necrosis factor (TNF)-related apoptosis-inducing ligand (sTRAIL) is a cancer cell-specific molecule exerting remarkable anti-tumour activities against paediatric malignancies both in vitro and in preclinical settings. However, due to its too fast elimination and to the undesired related side effects, the improvement of sTRAIL in vivo bioavailability and the specific delivery to the tumour is mandatory for increasing its therapeutic efficacy. In this manuscript, we developed an innovative pegylated liposomal formulation carrying the sTRAIL at the outer surface (sTRAIL-SL) with the intent to improve its serum half-life and increase its efficacy in vivo, while reducing side effects. Furthermore, the possibility to combine sTRAIL-SL with the proteasome inhibitor Bortezomib (BTZ) was investigated, being BTZ able to sensitize tumour cells toward TRAIL-induced apoptosis. We demonstrated that sTRAIL preserved and improved its anti-tumour activity when coupled to nanocarriers. Moreover, sTRAIL-SL ameliorated its PK profile in blood allowing sTRAIL to exert a more potent anti-tumour activity, which led, upon BTZ priming, to a statistically significant enhanced life spans in two models of sTRAIL-resistant NB-bearing mice. Finally, mechanistic studies indicated that the combination of sTRAIL with BTZ sensitized sTRAIL-resistant NB tumour cells to sTRAIL-induced cell death, both in vitro and in vivo, through the Akt/GSK3/β-catenin axis-dependent mechanism. In conclusion, our results suggest that sTRAIL-SL might be an efficient vehicle for sTRAIL delivery and that its use in clinic, in combination with BTZ, might represent an adjuvant strategy for the treatment of stage IV, sTRAIL-resistant, NB patients.
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Neuroblastoma (NB) is the most common extracranial solid tumor in childhood and the most frequently diagnosed neoplasm during infancy. Despite of aggressive treatment strategies, the 5-year survival rate for metastatic disease is still... more
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood and the most frequently diagnosed neoplasm during infancy. Despite of aggressive treatment strategies, the 5-year survival rate for metastatic disease is still less than 60% and, consequently, novel therapeutic approaches are needed. For increasing the therapeutic index of anticancer drugs, while reducing side effects, one of the most promising strategies in modern chemotherapy is based on the development of innovative drug delivery systems, such as liposomes. "Anticancer drug"-loaded liposomes have demonstrated enhanced ability to target to the affected area, as well as increased antitumor efficacy compared to conventional drugs. Liposomes tend to extravasate preferentially and to accumulate into tumor interstitial fluids, due to the defective structure of the new angiogenic vessels within the tumor masses. This inherent tumor selectivity can be increased further by coupling tumor-specific antibodies or other targeting moieties to the surface of the lipid envelope. Here, we describe the methodology used in these studies, as well as the antitumor results obtained by the use of several "anticancer drugs," encapsulated into antibody- and peptide-targeted liposomal formulations, against NB.
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Research Interests: Pharmacology, Nanoparticles, Gene Silencing, Biological Sciences, Molecular, and 15 moreRNA interference, Cell line, Humans, Mice, Animals, Cell Death, Neuroblastoma, Delivery System, Side Effect, Antitumor Activity, Molecular Targeted Therapy, Receptor Tyrosine Kinase, Cell Growth, reverse transcriptase polymerase chain reaction, and Medical and Health Sciences
The anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is involved in the pathogenesis of different types of human cancers, including neuroblastoma (NB). In NB, ALK overexpression, or point mutations, are associated with... more
The anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is involved in the pathogenesis of different types of human cancers, including neuroblastoma (NB). In NB, ALK overexpression, or point mutations, are associated with poor prognosis and advanced stage disease. Inhibition of ALK kinase activity by small-molecule inhibitors in lung cancers carrying ALK translocations has shown therapeutic potential. However, secondary mutations may occur that, generate tumor resistance to ALK inhibitors. To overcome resistance to ALK inhibitors in NB, we adopted an alternative RNA interference (RNAi)-based therapeutic strategy that is able to knockdown ALK, regardless of its genetic status [mutated, amplified, wild-type (WT)]. NB cell lines, transduced by lentiviral short hairpin RNA (shRNA), showed reduced proliferation and increased apoptosis when ALK was knocked down. In mice, a nanodelivery system for ALK-specific small interfering RNA (siRNA), based on the conjugation of antibodies directed against the NB-selective marker GD(2) to liposomes, showed strong ALK knockdown in vivo in NB cells, which resulted in cell growth arrest, apoptosis, and prolonged survival. ALK knockdown was associated with marked reductions in vascular endothelial growth factor (VEGF) secretion, blood vessel density, and matrix metalloproteinases (MMPs) expression in vivo, suggesting a role for ALK in NB-induced neoangiogenesis and tumor invasion, confirming this gene as a fundamental oncogene in NB.
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Research Interests: Biomedical Engineering, Cancer, Immunohistochemistry, Humans, Controlled release, and 15 moreEndothelial Cells, Mice, Female, Animals, Ligand Binding, Liposomes, Liposome, Efficiency, Doxorubicin, Endothelial cell, Combination drug therapy, Life Span, Drug Compounding, Ligands, and Combination Therapy
Molecular targeting of drug delivery nanocarriers is expected to improve their therapeutic index while decreasing their toxicity. Here we report the identification and characterization of novel peptide ligands specific for cells present... more
Molecular targeting of drug delivery nanocarriers is expected to improve their therapeutic index while decreasing their toxicity. Here we report the identification and characterization of novel peptide ligands specific for cells present in high-risk neuroblastoma (NB), a childhood tumor mostly refractory to current therapies. To isolate such targeting moieties, we performed combined in vitro/ex-vivo phage display screenings on NB cell lines and on tumors derived from orthotopic mouse models of human NB. By designing proper subtractive protocols, we identified phage clones specific either for the primary tumor, its metastases, or for their respective stromal components. Globally, we isolated 121 phage-displayed NB-binding peptides: 26 bound the primary tumor, 15 the metastatic mass, 57 and 23 their respective microenvironments. Of these, five phage clones were further validated for their specific binding ex-vivo to biopsies from stage IV NB patients and to NB tumors derived from mice. All five clones also targeted tumor cells and vasculature in vivo when injected into NB-bearing mice. Coupling of the corresponding targeting peptides with doxorubicin-loaded liposomes led to a significant inhibition in tumor volume and enhanced survival in preclinical NB models, thereby paving the way to their clinical development.
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The central problem in cancer chemotherapy is the severe toxic side effects of anticancer drugs on healthy tissues. The use of liposomes as drug delivery vehicles for antitumour therapeutics has great potential to revolutionise the future... more
The central problem in cancer chemotherapy is the severe toxic side effects of anticancer drugs on healthy tissues. The use of liposomes as drug delivery vehicles for antitumour therapeutics has great potential to revolutionise the future of cancer therapy. As tumour architecture causes liposomes to preferentially accumulate at the tumour site, their use as drug carriers results in the localization of a greater amount of the loaded drug at the tumour site, thus improving cancer therapy and reducing the harmful non-specific side effects of chemotherapeutics. In addition, targeting of liposomal anticancer drugs to antigens expressed or over-expressed on tumour cells provides a very efficient system for increasing the therapeutic indices of the drugs. Animal models allow detailed examination of molecular and physiological basis of diseases and offer a frontline testing system for studying the involvement of specific genes and the efficacy of novel therapeutic approaches. Until recently, the most resorted experimental model of paediatric Neuroblastoma (NB) tumour is the subcutaneous xenograft in nude mice. However, the main disadvantage of this animal model is that it does not reflect the metastatic potential of NB cells, ultimately responsible for poor patient survival. A more realistic view of the clinical potential of targeted therapies could be obtained if a tumour model were available that better reflects the growth of advanced NB in children (i.e. large adrenal gland tumours and multiple small metastatic lesions). All current data support this concept and recommend that orthotopic implantation of tumour cells in recipient animals is mandatory for studies of tumour progression, angiogenesis, invasion, and metastasis. This review will focus on the description of the most clinically relevant animal models established to test the efficacy of targeted liposomal anti-tumour formulations for the treatment of Neuroblastoma.
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Novel anti-vasculature strategies that are emerging for the treatment of cancer and for the inhibition of angiogenesis may be a promising new tool for the adjuvant therapy of malignant tumours. Over the last fifteen years, several reports... more
Novel anti-vasculature strategies that are emerging for the treatment of cancer and for the inhibition of angiogenesis may be a promising new tool for the adjuvant therapy of malignant tumours. Over the last fifteen years, several reports have been published concerning the relationship between tumour progression and angiogenesis in experimental models of neuroblastoma in vitro and in vivo. Moreover, a high vascular index in neuroblastoma correlates with poor prognosis, suggesting dependence of aggressive tumour growth on active angiogenesis. Here, we present an overview of the most recent advances in anti-vasculature therapy of neuroblastoma, and describe some preclinical results as well as future perspectives.