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Hyaluronic acid-tagged silica nanoparticles in colon cancer therapy: therapeutic efficacy evaluation.

Liu K, Wang ZQ, Wang SJ, Liu P, Qin YH, Ma Y, Li XC, Huo ZJ - Int J Nanomedicine (2015)

Bottom Line: The HA-conjugated nanoparticles provide the possibility of efficient drug transport into tumors that could effectively reduce the side effects in the normal tissues. 5-FU/HSNP was highly efficient in suppressing the tumor growth in xenograft tumor model.The proportion of Ki67 in 5-FU/HSNP-treated group was significantly lower than that of either free drug or nontargeted SiNPs.Altogether, we have showed that conjugation of HA to SiNPs could result in enhanced uptake of 5-FU through CD44-mediated endocytosis uptake and could result in significant antitumor efficacy.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People's Republic of China.

ABSTRACT
Colon cancer is one of the leading causes of cancer-related death worldwide, and the therapeutic application of 5-fluorouracil (5-FU) is limited due to its nonspecificity, low bioavailability, and overdose. The present study is an attempt to improve the chemotherapeutic efficacy of 5-FU in colon cancers. Therefore, we have prepared 5-FU-loaded hyaluronic acid (HA)-conjugated silica nanoparticles (SiNPs) to target to colon cancer cells. In this study, we have showed the specific binding and intracellular accumulation of targeted nanoparticles based on HA surface modifications in colon carcinoma cells. The particles had spherical shapes with sizes of approximately 130 nm. HA-conjugated nanoparticles showed a sustained release pattern for 5-FU and continuously released for 120 hours. We have further investigated the cytotoxicity potential of targeted and nontargeted nanoparticles in colo-205 cancer cells. IC50 value of 5-FU/hyaluronic acid-conjugated silica nanoparticles (HSNP) was 0.65 µg/mL compared with ~2.8 µg/mL for 5-FU/SNP after 24 hours of incubation. The result clearly showed that HA-conjugated NP was more effective in inducing apoptosis in cancer cells than nontargeted NP. The 5-FU/HSNP showed ~45% of cell apoptosis (early and late apoptosis stage) compared with only 20% for 5-FU/silica nanoparticles (SNP)-treated group. The HA-conjugated nanoparticles provide the possibility of efficient drug transport into tumors that could effectively reduce the side effects in the normal tissues. 5-FU/HSNP was highly efficient in suppressing the tumor growth in xenograft tumor model. The proportion of Ki67 in 5-FU/HSNP-treated group was significantly lower than that of either free drug or nontargeted SiNPs. Altogether, we have showed that conjugation of HA to SiNPs could result in enhanced uptake of 5-FU through CD44-mediated endocytosis uptake and could result in significant antitumor efficacy. Thus, 5-FU/HSNP could be a promising drug delivery system for colon cancer therapy.

No MeSH data available.


Related in: MedlinePlus

Annexin V-FITC FACS apoptosis analysis of HN6 cancer cells after treatment with free 5-FU, 5-FU/SNP, and 5-FU/HSNP for 24 hours and 48 hours.Notes: *P<0.05, **P<0.01.Abbreviations: FACS, fluorescence-activated cell sorting; 5-FU, 5-fluorouracil; HSNP, hyaluronic acid-conjugated silica nanoparticles; SNP, silica nanoparticles.
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f7-ijn-10-6445: Annexin V-FITC FACS apoptosis analysis of HN6 cancer cells after treatment with free 5-FU, 5-FU/SNP, and 5-FU/HSNP for 24 hours and 48 hours.Notes: *P<0.05, **P<0.01.Abbreviations: FACS, fluorescence-activated cell sorting; 5-FU, 5-fluorouracil; HSNP, hyaluronic acid-conjugated silica nanoparticles; SNP, silica nanoparticles.

Mentions: The quantitative apoptosis analysis was investigated by Annexin V-FITC/PI staining assay. Annexin V/FITC detects the phosphatidylserine externalization, which characterizes early apoptotic events. Cancer cell death can be programed (apoptosis) or nonprogramed (necrosis). The apoptosis-inducing effect of formulations was evaluated by counting the early apoptosis and late apoptosis (Figure 7). The result clearly showed that HA-conjugated NP was more effective in inducing apoptosis in cancer cells than nontargeted NP. For example, 5-FU/HSNP showed ~45% of cell apoptosis (early and late apoptosis stage) compared with only 20% for 5-FU/SNP-treated group. The result was consistent with the cellular uptake study, where HA-conjugated NP showed an enhanced cellular uptake. 5-FU, being a pyrimidine analogue, gets metabolized into different cytotoxic metabolites such as fluorodeoxyuridine monophosphate (FdUMP), fluoro-deoxyuridine triphosphate (FdUTP), and fluorouridine triphosphate (FUTP) inside the cells. These derivatives incorporate into DNA and RNA leading to cell death. One of the cytotoxic metabolites, FdUMP, blocks the synthesis of pyrimidine thymidine, which is required for DNA replication. The effectiveness of HSNP has been successfully proved in our study, which makes HA-conjugated NP a promising source for colon cancer therapy with high antitumor activity.


Hyaluronic acid-tagged silica nanoparticles in colon cancer therapy: therapeutic efficacy evaluation.

Liu K, Wang ZQ, Wang SJ, Liu P, Qin YH, Ma Y, Li XC, Huo ZJ - Int J Nanomedicine (2015)

Annexin V-FITC FACS apoptosis analysis of HN6 cancer cells after treatment with free 5-FU, 5-FU/SNP, and 5-FU/HSNP for 24 hours and 48 hours.Notes: *P<0.05, **P<0.01.Abbreviations: FACS, fluorescence-activated cell sorting; 5-FU, 5-fluorouracil; HSNP, hyaluronic acid-conjugated silica nanoparticles; SNP, silica nanoparticles.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608620&req=5

f7-ijn-10-6445: Annexin V-FITC FACS apoptosis analysis of HN6 cancer cells after treatment with free 5-FU, 5-FU/SNP, and 5-FU/HSNP for 24 hours and 48 hours.Notes: *P<0.05, **P<0.01.Abbreviations: FACS, fluorescence-activated cell sorting; 5-FU, 5-fluorouracil; HSNP, hyaluronic acid-conjugated silica nanoparticles; SNP, silica nanoparticles.
Mentions: The quantitative apoptosis analysis was investigated by Annexin V-FITC/PI staining assay. Annexin V/FITC detects the phosphatidylserine externalization, which characterizes early apoptotic events. Cancer cell death can be programed (apoptosis) or nonprogramed (necrosis). The apoptosis-inducing effect of formulations was evaluated by counting the early apoptosis and late apoptosis (Figure 7). The result clearly showed that HA-conjugated NP was more effective in inducing apoptosis in cancer cells than nontargeted NP. For example, 5-FU/HSNP showed ~45% of cell apoptosis (early and late apoptosis stage) compared with only 20% for 5-FU/SNP-treated group. The result was consistent with the cellular uptake study, where HA-conjugated NP showed an enhanced cellular uptake. 5-FU, being a pyrimidine analogue, gets metabolized into different cytotoxic metabolites such as fluorodeoxyuridine monophosphate (FdUMP), fluoro-deoxyuridine triphosphate (FdUTP), and fluorouridine triphosphate (FUTP) inside the cells. These derivatives incorporate into DNA and RNA leading to cell death. One of the cytotoxic metabolites, FdUMP, blocks the synthesis of pyrimidine thymidine, which is required for DNA replication. The effectiveness of HSNP has been successfully proved in our study, which makes HA-conjugated NP a promising source for colon cancer therapy with high antitumor activity.

Bottom Line: The HA-conjugated nanoparticles provide the possibility of efficient drug transport into tumors that could effectively reduce the side effects in the normal tissues. 5-FU/HSNP was highly efficient in suppressing the tumor growth in xenograft tumor model.The proportion of Ki67 in 5-FU/HSNP-treated group was significantly lower than that of either free drug or nontargeted SiNPs.Altogether, we have showed that conjugation of HA to SiNPs could result in enhanced uptake of 5-FU through CD44-mediated endocytosis uptake and could result in significant antitumor efficacy.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People's Republic of China.

ABSTRACT
Colon cancer is one of the leading causes of cancer-related death worldwide, and the therapeutic application of 5-fluorouracil (5-FU) is limited due to its nonspecificity, low bioavailability, and overdose. The present study is an attempt to improve the chemotherapeutic efficacy of 5-FU in colon cancers. Therefore, we have prepared 5-FU-loaded hyaluronic acid (HA)-conjugated silica nanoparticles (SiNPs) to target to colon cancer cells. In this study, we have showed the specific binding and intracellular accumulation of targeted nanoparticles based on HA surface modifications in colon carcinoma cells. The particles had spherical shapes with sizes of approximately 130 nm. HA-conjugated nanoparticles showed a sustained release pattern for 5-FU and continuously released for 120 hours. We have further investigated the cytotoxicity potential of targeted and nontargeted nanoparticles in colo-205 cancer cells. IC50 value of 5-FU/hyaluronic acid-conjugated silica nanoparticles (HSNP) was 0.65 µg/mL compared with ~2.8 µg/mL for 5-FU/SNP after 24 hours of incubation. The result clearly showed that HA-conjugated NP was more effective in inducing apoptosis in cancer cells than nontargeted NP. The 5-FU/HSNP showed ~45% of cell apoptosis (early and late apoptosis stage) compared with only 20% for 5-FU/silica nanoparticles (SNP)-treated group. The HA-conjugated nanoparticles provide the possibility of efficient drug transport into tumors that could effectively reduce the side effects in the normal tissues. 5-FU/HSNP was highly efficient in suppressing the tumor growth in xenograft tumor model. The proportion of Ki67 in 5-FU/HSNP-treated group was significantly lower than that of either free drug or nontargeted SiNPs. Altogether, we have showed that conjugation of HA to SiNPs could result in enhanced uptake of 5-FU through CD44-mediated endocytosis uptake and could result in significant antitumor efficacy. Thus, 5-FU/HSNP could be a promising drug delivery system for colon cancer therapy.

No MeSH data available.


Related in: MedlinePlus