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Sequential delivery of an anticancer drug and combined immunomodulatory nanoparticles for efficient chemoimmunotherapy.

Heo MB, Kim SY, Yun WS, Lim YT - Int J Nanomedicine (2015)

Bottom Line: However, CpG ODNs also induced the secretion of interleukin-10 (IL-10) that reduces the Th1 response and enhances the T helper 2 (Th2) response.Treatment of BMDCs with both types of PLGA NPs increased the Th1/Th2 cytokine (IL-12/IL-10) expression ratio, which is important for the effective induction of an antitumor immune response.After primary injection with the HA/PTX complex, the tumor-associated antigen was generated and taken up by tumor-recruited BMDCs.

View Article: PubMed Central - PubMed

Affiliation: SKKU Advanced Institute of Nanotechnology (SAINT), School of Chemical Engineering, Sungkyunkwan University, Suwon, Republic of Korea ; Center for Nanosafety Metrology, Division of Convergence Technology, Korea Research Institute of Standards and Science, Daejeon, Republic of Korea.

ABSTRACT
Chemoimmunotherapy combines chemotherapy based on anticancer drugs with immunotherapy based on immune activators to eliminate or inhibit the growth of cancer cells. In this study, water-insoluble paclitaxel (PTX) was dispersed in water using hyaluronic acid (HA) to generate a tumor-associated antigen in the tumor microenvironment. Cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) were used to enhance the T helper (Th) 1 immune response. However, CpG ODNs also induced the secretion of interleukin-10 (IL-10) that reduces the Th1 response and enhances the T helper 2 (Th2) response. Therefore, RNA interference was used to downregulate IL-10 secretion from bone marrow-derived den-dritic cells (BMDCs). For the combined immunomodulation of BMDCs, we fabricated two types of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing CpG ODNs to activate BMDCs via Toll-like receptor 9 (CpG ODN-encapsulated PLGA NPs, PCNs) or a small interfering RNA to silence IL-10 (IL-10 small interfering RNA-encapsulated PLGA NPs, PINs). Treatment of BMDCs with both types of PLGA NPs increased the Th1/Th2 cytokine (IL-12/IL-10) expression ratio, which is important for the effective induction of an antitumor immune response. After primary injection with the HA/PTX complex, the tumor-associated antigen was generated and taken up by tumor-recruited BMDCs. After a secondary injection with immunomodulating PCNs and PINs, the BMDCs became activated and migrated to the tumor-draining lymph nodes. As a result, the combination of chemotherapy using the HA/PTX complex and immunotherapy using PCNs and PINs not only efficiently inhibited tumor growth but also increased the animal survival rate. Taken together, our results suggest that the sequential treatment of cancer cells with a chemotherapeutic agent and immunomodulatory nanomaterials represents a promising strategy for efficient cancer therapy.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration of the sequential delivery of a chemotherapeutic drug (HA/PTX) followed by immunomodulatory PLGA NPs (PCNs and PINs) as a chemoimmunotherapy.Notes: Water-insoluble PTX was dispersed in water using HA to generate a TAA in the tumor microenvironment. For combined immunomodulation of BMDCs, we fabricated two types of PLGA NPs that contained CpG ODNs for the activation of BMDCs via TLR9 (CpG ODN-encapsulated PLGA NPs, PCNs) and siRNA for the silencing of IL-10 expression (IL-10 siRNA-encapsulated PLGA NPs, PINs).Abbreviations: HA, hyaluronic acid; PTX, paclitaxel; PLGA, poly(lactic-co-glycolic acid); NP, nanoparticle; TAA, tumor-associated antigen; BMDC, bone marrow-derived dendritic cell; CpG ODN, cytosine–phosphate–guanosine oligodeoxynucleotides; TLR, Toll-like receptor; siRNA, small interfering RNA; IL, interleukin.
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f1-ijn-10-5981: Schematic illustration of the sequential delivery of a chemotherapeutic drug (HA/PTX) followed by immunomodulatory PLGA NPs (PCNs and PINs) as a chemoimmunotherapy.Notes: Water-insoluble PTX was dispersed in water using HA to generate a TAA in the tumor microenvironment. For combined immunomodulation of BMDCs, we fabricated two types of PLGA NPs that contained CpG ODNs for the activation of BMDCs via TLR9 (CpG ODN-encapsulated PLGA NPs, PCNs) and siRNA for the silencing of IL-10 expression (IL-10 siRNA-encapsulated PLGA NPs, PINs).Abbreviations: HA, hyaluronic acid; PTX, paclitaxel; PLGA, poly(lactic-co-glycolic acid); NP, nanoparticle; TAA, tumor-associated antigen; BMDC, bone marrow-derived dendritic cell; CpG ODN, cytosine–phosphate–guanosine oligodeoxynucleotides; TLR, Toll-like receptor; siRNA, small interfering RNA; IL, interleukin.

Mentions: A combined chemoimmunotherapeutic approach may be beneficial for the efficient elimination of cancer. Chemotherapy using anticancer drugs can kill the tumor cells, causing the cancer to shrink. As a result, tumor-derived antigens, such as whole tumor cells, peptides, or proteins isolated from the tumor cells, can be efficiently internalized by APCs, thereby increasing the antitumor immunity of CTLs.34,35 In this in vivo study, we sequentially subjected tumor-bearing mice to chemotherapy consisting of PTX dissolved in hyaluronic acid (HA) and to immunotherapy using CpG ODNs and IL-10 siRNA incorporated into poly(lactic-co-glycolic acid) (PLGA) NPs (Figure 1). The sequential treatment with chemotherapeutic drugs followed by a combined immunostimulation strategy resulted in a synergistic effect against solid tumors. The Institutional Review Board of the Sungkyunkwan University does not require approvals for these case studies.


Sequential delivery of an anticancer drug and combined immunomodulatory nanoparticles for efficient chemoimmunotherapy.

Heo MB, Kim SY, Yun WS, Lim YT - Int J Nanomedicine (2015)

Schematic illustration of the sequential delivery of a chemotherapeutic drug (HA/PTX) followed by immunomodulatory PLGA NPs (PCNs and PINs) as a chemoimmunotherapy.Notes: Water-insoluble PTX was dispersed in water using HA to generate a TAA in the tumor microenvironment. For combined immunomodulation of BMDCs, we fabricated two types of PLGA NPs that contained CpG ODNs for the activation of BMDCs via TLR9 (CpG ODN-encapsulated PLGA NPs, PCNs) and siRNA for the silencing of IL-10 expression (IL-10 siRNA-encapsulated PLGA NPs, PINs).Abbreviations: HA, hyaluronic acid; PTX, paclitaxel; PLGA, poly(lactic-co-glycolic acid); NP, nanoparticle; TAA, tumor-associated antigen; BMDC, bone marrow-derived dendritic cell; CpG ODN, cytosine–phosphate–guanosine oligodeoxynucleotides; TLR, Toll-like receptor; siRNA, small interfering RNA; IL, interleukin.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4590313&req=5

f1-ijn-10-5981: Schematic illustration of the sequential delivery of a chemotherapeutic drug (HA/PTX) followed by immunomodulatory PLGA NPs (PCNs and PINs) as a chemoimmunotherapy.Notes: Water-insoluble PTX was dispersed in water using HA to generate a TAA in the tumor microenvironment. For combined immunomodulation of BMDCs, we fabricated two types of PLGA NPs that contained CpG ODNs for the activation of BMDCs via TLR9 (CpG ODN-encapsulated PLGA NPs, PCNs) and siRNA for the silencing of IL-10 expression (IL-10 siRNA-encapsulated PLGA NPs, PINs).Abbreviations: HA, hyaluronic acid; PTX, paclitaxel; PLGA, poly(lactic-co-glycolic acid); NP, nanoparticle; TAA, tumor-associated antigen; BMDC, bone marrow-derived dendritic cell; CpG ODN, cytosine–phosphate–guanosine oligodeoxynucleotides; TLR, Toll-like receptor; siRNA, small interfering RNA; IL, interleukin.
Mentions: A combined chemoimmunotherapeutic approach may be beneficial for the efficient elimination of cancer. Chemotherapy using anticancer drugs can kill the tumor cells, causing the cancer to shrink. As a result, tumor-derived antigens, such as whole tumor cells, peptides, or proteins isolated from the tumor cells, can be efficiently internalized by APCs, thereby increasing the antitumor immunity of CTLs.34,35 In this in vivo study, we sequentially subjected tumor-bearing mice to chemotherapy consisting of PTX dissolved in hyaluronic acid (HA) and to immunotherapy using CpG ODNs and IL-10 siRNA incorporated into poly(lactic-co-glycolic acid) (PLGA) NPs (Figure 1). The sequential treatment with chemotherapeutic drugs followed by a combined immunostimulation strategy resulted in a synergistic effect against solid tumors. The Institutional Review Board of the Sungkyunkwan University does not require approvals for these case studies.

Bottom Line: However, CpG ODNs also induced the secretion of interleukin-10 (IL-10) that reduces the Th1 response and enhances the T helper 2 (Th2) response.Treatment of BMDCs with both types of PLGA NPs increased the Th1/Th2 cytokine (IL-12/IL-10) expression ratio, which is important for the effective induction of an antitumor immune response.After primary injection with the HA/PTX complex, the tumor-associated antigen was generated and taken up by tumor-recruited BMDCs.

View Article: PubMed Central - PubMed

Affiliation: SKKU Advanced Institute of Nanotechnology (SAINT), School of Chemical Engineering, Sungkyunkwan University, Suwon, Republic of Korea ; Center for Nanosafety Metrology, Division of Convergence Technology, Korea Research Institute of Standards and Science, Daejeon, Republic of Korea.

ABSTRACT
Chemoimmunotherapy combines chemotherapy based on anticancer drugs with immunotherapy based on immune activators to eliminate or inhibit the growth of cancer cells. In this study, water-insoluble paclitaxel (PTX) was dispersed in water using hyaluronic acid (HA) to generate a tumor-associated antigen in the tumor microenvironment. Cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) were used to enhance the T helper (Th) 1 immune response. However, CpG ODNs also induced the secretion of interleukin-10 (IL-10) that reduces the Th1 response and enhances the T helper 2 (Th2) response. Therefore, RNA interference was used to downregulate IL-10 secretion from bone marrow-derived den-dritic cells (BMDCs). For the combined immunomodulation of BMDCs, we fabricated two types of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing CpG ODNs to activate BMDCs via Toll-like receptor 9 (CpG ODN-encapsulated PLGA NPs, PCNs) or a small interfering RNA to silence IL-10 (IL-10 small interfering RNA-encapsulated PLGA NPs, PINs). Treatment of BMDCs with both types of PLGA NPs increased the Th1/Th2 cytokine (IL-12/IL-10) expression ratio, which is important for the effective induction of an antitumor immune response. After primary injection with the HA/PTX complex, the tumor-associated antigen was generated and taken up by tumor-recruited BMDCs. After a secondary injection with immunomodulating PCNs and PINs, the BMDCs became activated and migrated to the tumor-draining lymph nodes. As a result, the combination of chemotherapy using the HA/PTX complex and immunotherapy using PCNs and PINs not only efficiently inhibited tumor growth but also increased the animal survival rate. Taken together, our results suggest that the sequential treatment of cancer cells with a chemotherapeutic agent and immunomodulatory nanomaterials represents a promising strategy for efficient cancer therapy.

No MeSH data available.


Related in: MedlinePlus