Combined anti-Galectin-1 and anti-EGFR siRNA-loaded chitosan-lipid nanocapsules decrease temozolomide resistance in glioblastoma: In vivo evaluation

Danhier, Fabienne; Messaoudi, Khaled; Lemaire, Laurent; Benoit, Jean‐Pierre; Lagarce, Frédéric

doi:10.1016/j.ijpharm.2015.01.051

Cited by 91 publications

(66 citation statements)

References 36 publications

(9 reference statements)

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“…The primary purpose of our work was to establish a proof-ofprinciple approach and to demonstrate that tumorigenesis can be antagonized using this vehicle and delivery strategy. Given that TFs and other genetic and epigenetic targets were considered "undruggable" by conventional pharmaceutical approaches, and nanomedicine-mediated RNAi strategies have been formulated primarily against membrane-bound or cytoplasmic effectors (29)(30)(31)(32)(33)(34)(35), this direct approach in delivering RNAi therapeutics to target tumorigenic gene circuits is a key step forward in diversifying our strategies against one of the most challenging human cancers.…”

mentioning

confidence: 91%

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Khan

Suvà

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

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Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood-brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTICtargeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.siRNA | lipopolymeric nanoparticle | glioblastoma transcription factor | brain tumor-initiating cells | convection-enhanced delivery G lioblastoma (GBM) is one of the most challenging tumors to treat (1, 2). Despite decades of research and maximal clinical combination therapy encompassing surgical resection, chemotherapy, and radiation, the median life expectancy of patients has not been extended beyond 2 y after diagnosis (2). Increasing evidence suggests that the genetic, epigenetic, and signaling heterogeneity of GBM underlies the ineffectiveness of currently available therapeutics (1, 2). Additionally, therapeutic schemes devised to challenge brain tumor cells are frequently thwarted by insufficient delivery caused by pharmacokinetics, the blood-brain barrier (BBB), and an altered tumor microenvironment in which tumor-derived signaling recruits immunomodulatory cells and induces extracellular matrix remodeling to build safe harbors of tumorigenic niches (3-5). These obstacles call for tailored therapeutic strategies to counter tumor heterogeneity and overcome roadblocks in delivery. RNAi targeting drivers of tumorigenesis shows strong potential to supplement the development of traditional small-molecule pharmaceutics (6). However, delivery remains a key obstacle for efficient RNAi against tumor drivers (5,7,8). RNA-sequencing analysis of patient tissue combined with histology and in situ hybridization (Ivy Glioblastoma Atlas Pro...

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mentioning

confidence: 91%

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Khan

Suvà

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

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“…The introduction of siRNAs directly into brain tumor tissues by the convection-enhanced delivery (CED) technique is a viable alternative to circumvent this obstacle (80). Combining CED with the use of nanoparticles for carrying siRNAs is a promising strategy to treat glioma tumors by RNAi (81)(82)(83). Finally, a sustained delivery of siRNAs implanted in tumor tissues would be of value to control aggressive cancer types.…”

Section: Discussionmentioning

confidence: 99%

Function of neuronal nitric oxide synthase enzyme in temozolomide-induced damage of astrocytic tumor cells

Resende

Titze‐de‐Almeida

2018

Oncol Lett

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Abstract. Astrocytic tumors, including astrocytomas and glioblastomas, are the most common type of primary brain tumors. Treatment for glioblastomas includes radiotherapy, chemotherapy with temozolomide (TMZ) and surgical ablation. Despite certain therapeutic advances, the survival time of patients is no longer than 12-14 months. Cancer cells overexpress the neuronal isoform of nitric oxide synthase (nNOS). In the present study, it was examined whether the nNOS enzyme serves a role in the damage of astrocytoma (U251MG and U138MG) and glioblastoma (U87MG) cells caused by TMZ. First, TMZ (250 µM) triggered an increase in oxidative stress at 2, 48 and 72 h in the U87MG, U251MG and U138MG cell lines, as revealed by 2',7'-dichlorofluorescin-diacetate assay. The drug also reduced cell viability, as measured by MTT assay. U87MG cells presented a more linear decline in cell viability at time-points 2, 48 and 72 h, compared with the U251MG and U138MG cell lines. The peak of oxidative stress occurred at 48 h. To examine the role of NOS enzymes in the cell damage caused by TMZ, N(ω)-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI) were used. L-NAME increased the cell damage caused by TMZ while reducing the oxidative stress at 48 h. The preferential nNOS inhibitor 7-NI also improved the TMZ effects. It caused a 12.8% decrease in the viability of TMZ-injured cells. Indeed, 7-NI was more effective than L-NAME in restraining the increase in oxidative stress triggered by TMZ. Silencing nNOS with a synthetic small interfering (si)RNA (siRNAnNOShum_4400) increased by 20% the effects of 250 µM of TMZ on cell viability (P<0.05). Hoechst 33342 nuclear staining confirmed that nNOS knock-down enhanced TMZ injury. In conclusion, our data reveal that nNOS enzymes serve a role in the damage produced by TMZ on astrocytoma and glioblastoma cells. RNA interference with nNOS merits further studies in animal models to disclose its potential use in brain tumor anticancer therapy.

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“…56,57 Studies have shown that nanomedicines can overcome tumor chemoresistance to alkylating agents. [58][59][60] For example, temozolomide, a commonly used alkylating agent, is considered the gold standard for the treatment of glioblastoma. 61,62 However, growing resistance to temozolomide remains a major clinical challenge.…”

Section: Alkylating Agentsmentioning

confidence: 99%

“…63,64 Messaoudi et al developed chitosan-grafted lipid nanocapsules to deliver both anti-EGFR and anti-Galectin-1 siRNA to tumor cells, which represents a promising strategy to overcome temozolomide resistance. 60,65,66 Patil et al synthesized multifunctional temozolomide nanoconjugates (6.5-14.8 nm) using poly(β-l-malic acid), which contained trileucine (LLL) and antibody to transferrin receptor. 58 It was found that temozolomide-resistant cells were sensitive to the temozolomide nanoconjugates, 58 clearly demonstrating the feasibility of overcoming tumor cell resistance to the alkylating agent temozolomide by formulating it into nanomedicine.…”

Section: Alkylating Agentsmentioning

confidence: 99%

Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

Chen¹,

Zheng²,

Shi³

et al. 2018

IJN

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Despite recent advances in targeted therapies and immunotherapies, chemotherapy using cytotoxic agents remains an indispensable modality in cancer treatment. Recently, there has been a growing emphasis in using nanomedicine in cancer chemotherapy, and several nanomedicines have already been used clinically to treat cancers. There is evidence that formulating small molecular cancer chemotherapeutic agents into nanomedicines significantly modifies their pharmacokinetics and often improves their efficacy. Importantly, cancer cells often develop resistance to chemotherapy, and formulating anticancer drugs into nanomedicines also helps overcome chemoresistance. In this review, we briefly describe the different classes of cancer chemotherapeutic agents, their mechanisms of action and resistance, and evidence of overcoming the resistance using nanomedicines. We then emphasize on gemcitabine and our experience in discovering the unique (stearoyl) gemcitabine solid lipid nanoparticles that are effective against tumor cells resistant to gemcitabine and elucidate the underlying mechanisms. It seems that lysosomes, which are an obstacle in the delivery of many drugs, are actually beneficial for our (stearoyl) gemcitabine solid lipid nanoparticles to overcome tumor cell resistance to gemcitabine.

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Combined anti-Galectin-1 and anti-EGFR siRNA-loaded chitosan-lipid nanocapsules decrease temozolomide resistance in glioblastoma: In vivo evaluation

Cited by 91 publications

References 36 publications

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Function of neuronal nitric oxide synthase enzyme in temozolomide-induced damage of astrocytic tumor cells

Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

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