Disseminated injection of vincristine-loaded silk gel improves the suppression of neuroblastoma tumor growth

Zeki, Jasmine; Taylor, Jordan S.; Yavuz, Burçin; Coburn, Jeannine M.; Ikegaki, Naohiko; Kaplan, David L.; Chiu, Bill

doi:10.1016/j.surg.2018.06.017

Cited by 14 publications

(10 citation statements)

References 21 publications

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“…Tumor size (500 mm 3 , 600 mm 3 , 700 mm 3 , or 800 mm 3 ) was calculated from these equations as previously described. [28] In brief, we solved for the post-operative day using the "goal seek" function under the "what-if analysis" (Microsoft Excel, 2011, version 14.7.4, Redmond, Washington). The postoperative days obtained for each given tumor size were compared using Student's t test, with p values <0.05 considered statistically significant.…”

Section: Discussionmentioning

confidence: 99%

“…[20] Minimally invasive techniques such as image guided injections could be adapted to deliver injectible anti-tumor therapy, providing additional benefits. [28] Alternatively, there is an opportunity for local delivery of anti-tumor therapy in a sustained release platform at the time of surgery to improve local control, particularly in the case of an incomplete resection. Previous studies have shown improved local control when local anti-tumor therapy is used in combination with a partial resection of neuroblastoma.…”

Section: Discussionmentioning

confidence: 99%

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Down-regulation of MYCN protein by CX-5461 leads to neuroblastoma tumor growth suppression

Taylor

Zeki

Ornell

et al. 2019

Journal of Pediatric Surgery

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Purpose: MYCN oncogene amplification is an independent predictor of poor prognosis in neuroblastoma. CX-5461 is a small molecular inhibitor that prevents initiation of ribosomal RNA (rRNA) synthesis by RNA Pol I, down-regulating MYCN/MYC proteins. We hypothesize that neuroblastoma tumor growth can be suppressed by CX-5461. Methods: MYCN-amplified (KELLY, IMR5) and non-amplified (SY5Y, SKNAS) neuroblastoma cells were treated with CX-5461. MYCN/MYC expression after 24-48 hours was determined by Western blot. Orthotopic neuroblastoma tumors created in mice using KELLY cells were treated with CX-5461-loaded silk films implanted locally. Tumor growth was monitored using ultrasound. Histologic evaluation of tumors was performed. Results: IC 50 for KELLY, IMR5, SY5Y, and SKNAS cells to CX-5461 was 0.75µM, 0.02µM, 0.8µM, and 1.7µM, respectively. CX-5461 down-regulated MYCN and MYC proteins at 0.25-1.0µM on Western blot analysis. CX-5461-loaded silk film released 23.7±3µg of the drug in 24 hours and 48.2±3.9µg at 120 hours. KELLY tumors treated with CX-5461-loaded film reached 800mm 3 after 7.8±1.4 days, while those treated with control film reached the same size on 5.1±0.6 days (p=0.03). CX-5461-treated tumors showed collapse of nucleolar hypertrophy and MYCN protein downregulation. Conclusion: We demonstrated that local delivery of CX-5461 via sustained release platform can suppress orthotopic neuroblastoma tumor growth, especially those with MYCN/MYC overexpression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Down-regulation of MYCN protein by CX-5461 leads to neuroblastoma tumor growth suppression

Taylor

Zeki

Ornell

et al. 2019

Journal of Pediatric Surgery

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“…Additionally, lyophilized silk has been shown to have a stabilizing effect on enzymes and other macromolecules, which is expected to extend to antibodies . The silk‐based platform for local delivery also offers the advantage of tailored release profile based on fabrication and distribution of treatment within the tumor bed …”

Section: Discussionmentioning

confidence: 99%

“…Silk fibroin is also a versatile substrate that can be fabricated into numerous forms suitable for various clinical situations. We have previously demonstrated that silk fibroin can be loaded with chemotherapy in an injectable gel form and can be administered locally via intra‐tumoral injections . This therapy could be administered at various stages of disease treatment: Initially, it could be administered via image‐guided (ultrasound or computed tomography scan) injection to complement other systemic therapy.…”

Section: Discussionmentioning

confidence: 99%

Local delivery of dinutuximab from lyophilized silk fibroin foams for treatment of an orthotopic neuroblastoma model

et al. 2020

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Immunotherapy targeting GD2 is a primary treatment for patients with high-risk neuroblastoma. Dinutuximab is a monoclonal antibody with great clinical promise but is limited by side effects such as severe pain. Local delivery has emerged as a potential mechanism to deliver higher doses of therapeutics into the tumor bed, while limiting systemic toxicity. We aim to deliver dinutuximab locally in a lyophilized silk fibroin foam for the treatment of an orthotopic neuroblastoma mouse model. Dinutuximabloaded silk fibroin foams were fabricated through lyophilization. In vitro release profile and bioactivity of the release through complement-dependent cytotoxicity were characterized. MYCN-amplified neuroblastoma cells (KELLY) were injected into the left gland of mice to generate an orthotopic neuroblastoma model. Once the tumor volume reached 100 mm 3 , dinutuximab-, human IgG-, or buffer-loaded foams were implanted into the tumor and growth was monitored using high-resolution ultrasound. Post-resection histology was performed on tumors. Dinutuximab-loaded silk fibroin foams exhibited a burst release, with slow release thereafter in vitro with maintenance of bioactivity. The dinutuximab-loaded foam significantly inhibited xenograft tumor growth compared to IgG-and buffer-loaded foams. Histological analysis revealed the presence of dinutuximab within the tumor and neutrophils and macrophages infiltrating into dinutuximab-loaded silk foam. Tumors treated with local dinutuximab had decreased MYCN expression on histology compared to control or IgG-treated tumors. Silk fibroin foams offer a mechanism for local release of dinutuximab within the neuroblastoma tumor. This local delivery achieved a significant decrease in tumor growth rate in a mouse orthotopic tumor model. K E Y W O R D SCh14.18, dinutuximab, immunotherapy, local delivery, neuroblastoma, silk fibroin

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“…Silk fibroin doesn't cause any inflammatory reaction and biocompatible following degumming process and therefore it can safely be applied via vaginal or rectal routes [8,9]. In addition to being a Food and Drug Administration (FDA) approved biomaterial as medical sutures and soft tissue scaffolds [10], silk has shown the ability to successfully deliver a wide range of bioactive molecules including antineoplastic drugs [11][12][13][14][15][16][17][18], antibiotics [19], antiepileptics [20], genes [21,22] and biological drugs such as growth factors [23] and antibodies [24]. Silk also increases the stability of drugs and biomacromolecules [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Sustained release silk fibroin discs: Antibody and protein delivery for HIV prevention

Yavuz

Morgan

Herrera

et al. 2019

Journal of Controlled Release

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With almost 2 million new HIV infections worldwide each year, the prevention of HIV infection is critical for stopping the pandemic. The only approved form of pre-exposure prophylaxis is a costly daily pill, and it is recognized that several options will be needed to provide protection to the various affected communities around the world. In particular, many at-risk people would benefit from a prevention method that is simple to use and does not require medical intervention or a strict daily regimen. We show that silk fibroin protein can be formulated into insertable discs that encapsulate either an antibody (IgG) or the potent HIV inhibitor 5P12-RANTES. Several formulations were studied, including silk layering, water vapor annealing and methanol treatment to stabilize the protein cargo and impact the release kinetics over weeks. In the case of IgG, high concentrations were released over a short time using methanol treatment, with more sustained results with the use of water vapor annealing and layering during device fabrication. For 5P12-RANTES, sustained release was obtained for 31 days using water vapor annealing. Further, we show that the released inhibitor 5P12-RANTES was functional both in vitro and in ex vivo colorectal tissue. This work shows that silk fibroin discs can be developed into formidable tools to prevent HIV infection.

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Disseminated injection of vincristine-loaded silk gel improves the suppression of neuroblastoma tumor growth

Abstract: Injecting vincristine-loaded sustained release silk gel at 8 separate locations halved the diffusion distance and doubled the time for the tumor to reach the growth inflexion point.

Cited by 14 publications

References 21 publications

Down-regulation of MYCN protein by CX-5461 leads to neuroblastoma tumor growth suppression

Down-regulation of MYCN protein by CX-5461 leads to neuroblastoma tumor growth suppression

Local delivery of dinutuximab from lyophilized silk fibroin foams for treatment of an orthotopic neuroblastoma model

Sustained release silk fibroin discs: Antibody and protein delivery for HIV prevention

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