Enhanced antitumor efficacy of poly(D,L-lactide-co-glycolide)-based methotrexate-loaded implants on sarcoma 180 tumor-bearing mice

Gao, Li; Xia, Lunyang; Zhang, Ruhui; Duan, Dandan; Liu, Xiuxiu; Juan, Xu; Luo, Liang

doi:10.2147/dddt.s143942

Cited by 14 publications

(8 citation statements)

References 29 publications

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“…In addition, most anti-cancer agents are not formulated specifically for intratumoral delivery as INT230-6 is. A recent study by Gao et al 2017, for example, investigates the efficacy of an intratumoral methotrexateloaded implant in a sarcoma model which caused delay in tumor growth, but the immune response was not investigated. 34 On the other hand, a clinical study by Yu et al 2015 compared intratumoral chemotherapy to ultraminimum incision personalized intratumoral chemoimmunotherapy which consisted of an oxidant, a cytotoxic drug (cytosine arabinoside) and hapten.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study by Gao et al 2017, for example, investigates the efficacy of an intratumoral methotrexateloaded implant in a sarcoma model which caused delay in tumor growth, but the immune response was not investigated. 34 On the other hand, a clinical study by Yu et al 2015 compared intratumoral chemotherapy to ultraminimum incision personalized intratumoral chemoimmunotherapy which consisted of an oxidant, a cytotoxic drug (cytosine arabinoside) and hapten. 35 The authors treated 97 patients with advanced lung cancer and found significantly improved overall survival with their chemoimmunotherapy.…”

Section: Discussionmentioning

confidence: 99%

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Intratumorally delivered formulation, INT230-6, containing potent anticancer agents induces protective T cell immunity and memory

Bloom

Bender²,

Tiwary

et al. 2019

OncoImmunology

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The benefits of anti-cancer agents extend beyond direct tumor killing. One aspect of cell death is the potential to release antigens that initiate adaptive immune responses. Here, a diffusion enhanced formulation, INT230-6, containing potent anti-cancer cytotoxic agents, was administered intratumorally into large (approx. 300mm 3) subcutaneous murine Colon26 tumors. Treatment resulted in regression from baseline in 100% of the tumors and complete response in up to 90%. CD8 + or CD8 + /CD4 + T cell double-depletion at treatment onset prevented complete responses, indicating a critical role of T cells in promoting complete tumor regression. Mice with complete response were protected from subcutaneous and intravenous re-challenge of Colon26 cells in a CD4 + /CD8 + dependent manner. Thus, immunological T cell memory was induced by INT230-6. Colon26 tumors express the endogenous retroviral protein gp70 containing the CD8 + T-cell AH-1 epitope. AH-1-specific CD8 + T cells were detected in peripheral blood of tumor-bearing mice and their frequency increased 14 days after treatment onset. AH-1-specific CD8 + T cells were also significantly enriched in tumors of untreated mice. These cells had an activated phenotype and highly expressed Programmed cell-death protein-1 (PD-1) but did not lead to tumor regression. CD8 + T cell tumor infiltrate also increased 11 days after treatment. INT230-6 synergized with checkpoint blockade, inducing a complete remission of the primary tumors and shrinking of untreated contralateral tumors, which demonstrates not only a local but also systemic immunological effect of the combined therapy. Similar T-cell dependent inhibition of tumor growth was also found in an orthotopic 4T1 breast cancer model.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intratumorally delivered formulation, INT230-6, containing potent anticancer agents induces protective T cell immunity and memory

Bloom

Bender²,

Tiwary

et al. 2019

OncoImmunology

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“…The cells were cultured at 37 °C in a humidified incubator in an atmosphere of 95% oxygen and 5% carbon dioxide. The cell suspension was adjusted to 1 × 10 7 cells/ml and 100 µl of the suspension was injected subcutaneously into the armpit of a right anterior limb of each mouse (Gao et al., 2017). The in vivo studies were started when the tumor volume reached 100–200 mm 3 .…”

Section: Methodsmentioning

confidence: 99%

The improved antitumor efficacy of continuous intratumoral chemotherapy with cisplatin-loaded implants for the treatment of sarcoma 180 tumor-bearing mice

Gao

Cai

et al. 2019

Drug Delivery

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Cisplatin is the most commonly used antitumor drug in the chemotherapy of a variety of malignancies. However, the severe side effects and drug resistance limit its clinical application. The aim of this study was to develop PLGA-based cisplatin-loaded implants and evaluate the antitumor efficacy of continuous intratumoral chemotherapy with the implants. The cisplatin-loaded implants were prepared by the direct compression method and characterized regarding drug content, micromorphology, in vitro and in vivo drug release profiles. Furthermore, the antitumor activity of the implants was conducted in sarcoma 180 tumor-bearing mice. The SEM images showed smooth surface of the implants and the mean drug content of the tested implants was (37.7% ± 0.5%, w/w). Both in vitro and in vivo release profiles of the implants were characterized by initial burst release followed by the sustained-release of cisplatin. Intratumoral implantation of the cisplatin-loaded implants could effectively inhibit the tumor growth. Additionally, intratumoral chemotherapy with the implants significantly reduced the systemic toxicity compared with intravenous injection of cisplatin. It is worth noting that an increase in the dose of the implants led to a higher tumor suppression rate without additional systemic toxicity. These results demonstrated that cisplatin-loaded implants enhanced the antitumor efficacy and reduced the dose-related side effects in sarcoma 180 tumor-bearing mice.

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“…[57] Also beta-lapachone-loaded polymer implants were used for the treatment of prostate cancer. [58] Other applications have included, composite liposome-in-gel systems as injectable drug depots, [59] injectable in situ formation of carboxymethyl chitin hydrogel implants for 3D cell culture, [60] PLGA based DOX-loaded implants for local DOX release, [61] poly(D,L-lactide-co-glycolide)-based methotrexateloaded implants for enhanced anti-tumor efficacy against sarcoma 180, [62] paclitaxel-loaded injectable in situ-forming gels, [63] and injectable in situ-forming hydrogels for osteogenic differentiation of human turbinate mesenchymal stem cells. [64] An advanced hydrogel based on self-assembling peptides tethered with RADA16-GGQQLK (QLK) and RADA16-GGLRK-KLGKA (LRK) sequences was synthesized to promote the formation of capillary-like tubular endothelial structures, as well as supporting the survival of the embedded cells.…”

Section: Hydrogels For Local (In Situ) Administrationmentioning

confidence: 99%

Potential Applications of Advanced Nano/Hydrogels in Biomedicine: Static, Dynamic, Multi‐Stage, and Bioinspired

Ayoubi‐Joshaghani

Seidi

Azizi

et al. 2020

Adv Funct Materials

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Novel advanced hydrogels can provide a versatile platform for controlled delivery and release of various cargos, with a myriad of biomedical applications. These gel-based nanostructures possess good biocompatibility, biodegradability, flexibility, multifunctionality, can respond to internal or external stimuli, and can adapt to their surrounding environment. This new generation of hydrogels is not only capable of serving as targeted drug delivery vehicles, but they can also perform a variety of tasks within living cells and organisms. In this review, advanced hydrogels are classified as static, dynamic, multistage, or bioinspired. They can be used as cell-free gene expression platforms for gene therapy. Administration of nanogel-based sprays can act as an immunovaccine priming macrophages toward the M1 phenotype to avoid cancer recurrence following surgery. Nanogels can also serve as a dual biosensing and capture platform for liquid biopsies, and can recognize and remove circulating cancer cells from the blood of cancer patients.

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Enhanced antitumor efficacy of poly(D,L-lactide-co-glycolide)-based methotrexate-loaded implants on sarcoma 180 tumor-bearing mice

Cited by 14 publications

References 29 publications

Intratumorally delivered formulation, INT230-6, containing potent anticancer agents induces protective T cell immunity and memory

Intratumorally delivered formulation, INT230-6, containing potent anticancer agents induces protective T cell immunity and memory

The improved antitumor efficacy of continuous intratumoral chemotherapy with cisplatin-loaded implants for the treatment of sarcoma 180 tumor-bearing mice

Potential Applications of Advanced Nano/Hydrogels in Biomedicine: Static, Dynamic, Multi‐Stage, and Bioinspired

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