Nanoparticle-Delivered Suicide Gene Therapy Effectively Reduces Ovarian Tumor Burden in Mice

Yu, Hongliang; Zugates, Gregory T.; Peng, Weidan; Holtz, David O.; Dunton, Charles J.; Green, Jordan J.; Hossain, Naushad; Chernick, Michael R.; Padera, Robert F.; Langer, Robert; Anderson, Daniel G.; Sawicki, Janet A.

doi:10.1158/0008-5472.can-09-0061

Cited by 82 publications

(71 citation statements)

References 21 publications

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“…Sawicki and Anderson have demonstrated the effectiveness of the i.p. mode of administration of polymeric nanoparticles to tailor delivery of DNA to encode diphtheria suicide protein for the treatment of advanced stage ovarian cancer (27). Indeed, there are several examples in the literature that illustrate the efficacy of the i.p.…”

Section: Resultsmentioning

confidence: 99%

Bombesin functionalized gold nanoparticles show in vitro and in vivo cancer receptor specificity

Chanda¹,

Kattumuri²,

Shukla³

et al. 2010

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

293

245

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Development of cancer receptor-specific gold nanoparticles will allow efficient targeting/optimum retention of engineered gold nanoparticles within tumors and thus provide synergistic advantages in oncology as it relates to molecular imaging and therapy. Bombesin (BBN) peptides have demonstrated high affinity toward gastrin-releasing peptide (GRP) receptors in vivo that are overexpressed in prostate, breast, and small-cell lung carcinoma. We have synthesized a library of GRP receptor-avid nanoplatforms by conjugating gold nanoparticles (AuNPs) with BBN peptides. Cellular interactions and binding affinities (IC 50 ) of AuNP-BBN conjugates toward GRP receptors on human prostate cancer cells have been investigated in detail. In vivo studies using AuNP-BBN and its radiolabeled surrogate 198 AuNP-BBN, exhibiting high binding affinity (IC 50 in microgram ranges), provide unequivocal evidence that AuNP-BBN constructs are GRP-receptor-specific showing accumulation with high selectivity in GRP-receptor-rich pancreatic acne in normal mice and also in tumors in prostate-tumor-bearing, severe combined immunodeficient mice. The i.p. mode of delivery has been found to be efficient as AuNP-BBN conjugates showed reduced RES organ uptake with concomitant increase in uptake at tumor targets. The selective uptake of this new generation of GRP-receptor-specific AuNP-BBN peptide analogs has demonstrated realistic clinical potential in molecular imaging via x-ray computed tomography techniques as the contrast numbers in prostate tumor sites are severalfold higher as compared to the pretreatment group (Hounsfield unit = 150).gold nanoparticles | bombesin | gastrin-releasing peptide receptor | prostate cancer | computed tomography imaging

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Section: Resultsmentioning

confidence: 99%

Bombesin functionalized gold nanoparticles show in vitro and in vivo cancer receptor specificity

Chanda¹,

Kattumuri²,

Shukla³

et al. 2010

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

293

245

View full text Add to dashboard Cite

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“…Genetically engineered tumor models arise in situ where immune function, angiogenesis, and inflammatory processes can all interact normally with a gradually developing tumor, closely relating to the clinical setting of the disease (6,7). Although these transgenic tumor models may be more appropriate for the evaluation of promising nanocarriers, only a few nanocarrier systems have been assessed on transgenic models so far (10)(11)(12)(13)(14)(15)(16)(17)(18)(19), mainly for imaging purposes (15)(16)(17)(18)(19).…”

mentioning

confidence: 99%

Targeted therapy of spontaneous murine pancreatic tumors by polymeric micelles prolongs survival and prevents peritoneal metastasis

Cabral¹,

Murakami²,

Hojo

et al. 2013

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

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Nanoscaled drug-loaded carriers are of particular interest for efficient tumor therapy as numerous studies have shown improved targeting and efficacy. Nevertheless, most of these studies have been performed against allograft and xenograft tumor models, which have altered microenvironment features affecting the accumulation and penetration of nanocarriers. Conversely, the evaluation of nanocarriers on genetically engineered mice, which can gradually develop clinically relevant tumors, permits the validation of their design under normal processes of immunity, angiogenesis, and inflammation. Therefore, considering the poor prognosis of pancreatic cancer, we used the elastase 1-promoted luciferase and Simian virus 40 T and t antigens transgenic mice, which develop spontaneous bioluminescent pancreatic carcinoma, and showed that long circulating micellar nanocarriers, incorporating the parent complex of oxaliplatin, inhibited the tumor growth as a result of their efficient accumulation and penetration in the tumors. The reduction of the photon flux from the endogenous tumor by the micelles correlated with the decrease of serum carbohydrate-associated antigen 19-9 marker. Micelles also reduced the incidence of metastasis and ascites, extending the survival of the transgenic mice.chemotherapy | drug delivery | (1,2-diaminocyclohexane)platinum (II)

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“…In this experiment, we developed a tumor-specific survivin promoter-driven phytotoxin protein expression vector for systemic liver cancer gene therapy. Our data demonstrated the superiority of our engineered pSur-Gel system had nearly no toxicity in normal tissues, but could effectively inhibited tumor growth [37].…”

Section: Discussionmentioning

confidence: 61%

“…Targeted gene therapies which use toxin to fight cancer might be a good strategy. Polymeric nanoparticles to deliver DT-A encoding DNA combined with transcriptional regulation to target gene expression to ovarian tumor cells, this strategy suppressed tumor growth more effectively than treatment with clinically relevant doses of cisplatin and paclitaxel [37]. However, no one take phytotoxin for gene therapy before.…”

Section: Discussionmentioning

confidence: 99%

Suppression of hepatoma tumor growth by systemic administration of the phytotoxin gelonin driven by the survivin promoter

Wang

Zhou²,

Li³

et al. 2013

neo

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Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide. However, there is currently no effective therapy strategy in the clinical practice. Recombinant phytotoxin gelonin fused to other factors have been used to treat different cancers. But there have been no reports of gelonin gene therapy. In this study, we have constructed a recombinant plasmid which contained a tumor-specific survivin promoter to drive phytotoxin gelonin (pSur-Gel). And the cytotoxicity effects of pSur-Gel in HCC were also validated both in vitro and in vivo. The expression level of survivin was detetected in different liver cancer cell lines and nomal liver cell lines by western blot analysis, and a survivin promoter-driven green fluorescent protein (GFP) expression vectors (pSur-GFP) was also tested in liver cancer cell line HepG2 and normal liver cell line LO2. Moreover, phytotoxin gelonin expression experiment and cytotoxicity experiment of pSur-Gel was performed in HepG2 cells and LO2 cells in vitro. Furthermore, anti-tumor effect of pSur-Gel against HepG2 xenografts and toxicity of this gene were evaluated in the mice model. Finally, LDH release assay, apoptosis assay and immunoblot analyse LC3 conversion (LC3-I to LC3-II) were tested. We found that the expression of survivin protein was higher in liver cancer cell lines compared with the normal liver cells. Further study showed that the pSur-GFP and pSur-Gel was expressed specially in liver cancer cell other than in normal liver cells. pSur-Gel plasmid could effectively inhibit the proliferation of liver cancer cells (*P<0.05), and significantly repress the growth of HepG2 xenografts via intravenous in vivo (*P<0.05). Otherwise, compared to cytomegalovirus promoter-driven gelonin expression vectors (pCMV-Gel), no significantly systemic toxicity or organ injuries had been observed in pSur-Gel treated mice. Further studies revealed that the phytotoxin gelonin induced cell death might be mediated by apoptosis and the damage of cell membrane. Taken together, treating hepatocellular carcinoma with the pSur-Gel may be a novel and interesting cancer gene therapy protocol and is worthy of further development for future clinical trials.

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Nanoparticle-Delivered Suicide Gene Therapy Effectively Reduces Ovarian Tumor Burden in Mice

Abstract: There is currently no effective therapy for patients with advanced ovarian cancer.

Cited by 82 publications

References 21 publications

Bombesin functionalized gold nanoparticles show in vitro and in vivo cancer receptor specificity

Bombesin functionalized gold nanoparticles show in vitro and in vivo cancer receptor specificity

Targeted therapy of spontaneous murine pancreatic tumors by polymeric micelles prolongs survival and prevents peritoneal metastasis

Suppression of hepatoma tumor growth by systemic administration of the phytotoxin gelonin driven by the survivin promoter

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