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Nonspecifically enhanced therapeutic effects of vincristine on multidrug-resistant cancers when coencapsulated with quinine in liposomes.

Xu Y, Qiu L - Int J Nanomedicine (2015)

Bottom Line: The antitumor effects of the formulation were also evaluated in multidrug-resistant tumor-bearing mice.The results of this in vivo study indicated that VQL could reverse VCR resistance.In addition, it reduced tumor volume 5.4-fold when compared with other test groups.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.

ABSTRACT
The use of vincristine (VCR) to treat cancer has been limited by its dose-dependent toxicity and development of drug resistance after repeated administrations. In this study, we investigated the mechanism by which quinine hydrochloride (QN) acts as a sensitizer for VCR. Our experiments used three kinds of multidrug-resistant cancer cells and demonstrated that QN worked by inducing intracellular depletion of adenosine triphosphate, increasing adenosine triphosphatase activity, and decreasing P-glycoprotein expression. Based on these results, we designed and prepared a VCR and QN codelivery liposome (VQL) and investigated the effect of coencapsulated QN on the in vitro cytotoxicity of VCR in cells and three-dimensional multicellular tumor spheroids. The antitumor effects of the formulation were also evaluated in multidrug-resistant tumor-bearing mice. The results of this in vivo study indicated that VQL could reverse VCR resistance. In addition, it reduced tumor volume 5.4-fold when compared with other test groups. The data suggest that VQL could be a promising nanoscaled therapeutic agent to overcome multidrug resistance, and may have important clinical implications for the treatment of cancer.

No MeSH data available.


Related in: MedlinePlus

Release profiles of VCR and QN from FVCR, FQN, VCRL, QNL, L1:1, L1:2 and VQL1:1, VQL1:2 in phosphate-buffered saline of pH 7.4 and 5.5 at 37°C.Notes: (A) pH 7.4 VCR, (B) pH 7.4 QN, (C) pH 5.5 VCR, and (D) pH 5.5 QN. Each condition was tested in triplicate. The standard deviation is presented as error bars.Abbreviations: VCR, vincristine; QN, quinine; FVCR, free vincristine; FQN, free quinine; VCRL, VCR liposome; QNL, QN liposome; L1:1, VCR liposome + QN liposome =1:1; L1:2, VCR liposome + QN liposome =1:2; VQL1:1, VCR and QN codelivery liposome with a ratio of 1:1; VQL1:2, VCR and QN codelivery liposome with a ratio of 1:2.
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f4-ijn-10-4225: Release profiles of VCR and QN from FVCR, FQN, VCRL, QNL, L1:1, L1:2 and VQL1:1, VQL1:2 in phosphate-buffered saline of pH 7.4 and 5.5 at 37°C.Notes: (A) pH 7.4 VCR, (B) pH 7.4 QN, (C) pH 5.5 VCR, and (D) pH 5.5 QN. Each condition was tested in triplicate. The standard deviation is presented as error bars.Abbreviations: VCR, vincristine; QN, quinine; FVCR, free vincristine; FQN, free quinine; VCRL, VCR liposome; QNL, QN liposome; L1:1, VCR liposome + QN liposome =1:1; L1:2, VCR liposome + QN liposome =1:2; VQL1:1, VCR and QN codelivery liposome with a ratio of 1:1; VQL1:2, VCR and QN codelivery liposome with a ratio of 1:2.

Mentions: An ideal liposome delivery system should be stable under physiological circulations but release the drug at the action site. The pH of blood is 7.4, and that of the intracellular microenvironment of tumor tissues is approximately 5.5.29 Therefore, the release of VCR and QN from FVCR, FQN, VCR liposomes, QN liposomes, L1:1, L1:2, VQL1:1, and VQL1:2 was examined in PBS of pH 7.4 and pH 5.5 at 37°C. As shown in Figure 4A and B, VCR liposomes and QN liposomes had a slower release rate than free VCR and free QN at pH 7.4, indicating that the liposome is capable of sustained drug release. When the pH of the release medium was decreased from 7.4 to 5.5, the release rate was more rapid for both drugs (Figure 4C and D). The cumulative drug release reached 70%–90% within the first 4 hours, suggesting that rapid drug release would occur as soon as the liposomes were endocytosed into the acidic endosomes of cancer cells. Furthermore, it was observed that QN was released a little faster than VCR at both pH values, which indicates that QN may reach the target site before VCR when they are coencapsulated in the same liposome.


Nonspecifically enhanced therapeutic effects of vincristine on multidrug-resistant cancers when coencapsulated with quinine in liposomes.

Xu Y, Qiu L - Int J Nanomedicine (2015)

Release profiles of VCR and QN from FVCR, FQN, VCRL, QNL, L1:1, L1:2 and VQL1:1, VQL1:2 in phosphate-buffered saline of pH 7.4 and 5.5 at 37°C.Notes: (A) pH 7.4 VCR, (B) pH 7.4 QN, (C) pH 5.5 VCR, and (D) pH 5.5 QN. Each condition was tested in triplicate. The standard deviation is presented as error bars.Abbreviations: VCR, vincristine; QN, quinine; FVCR, free vincristine; FQN, free quinine; VCRL, VCR liposome; QNL, QN liposome; L1:1, VCR liposome + QN liposome =1:1; L1:2, VCR liposome + QN liposome =1:2; VQL1:1, VCR and QN codelivery liposome with a ratio of 1:1; VQL1:2, VCR and QN codelivery liposome with a ratio of 1:2.
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f4-ijn-10-4225: Release profiles of VCR and QN from FVCR, FQN, VCRL, QNL, L1:1, L1:2 and VQL1:1, VQL1:2 in phosphate-buffered saline of pH 7.4 and 5.5 at 37°C.Notes: (A) pH 7.4 VCR, (B) pH 7.4 QN, (C) pH 5.5 VCR, and (D) pH 5.5 QN. Each condition was tested in triplicate. The standard deviation is presented as error bars.Abbreviations: VCR, vincristine; QN, quinine; FVCR, free vincristine; FQN, free quinine; VCRL, VCR liposome; QNL, QN liposome; L1:1, VCR liposome + QN liposome =1:1; L1:2, VCR liposome + QN liposome =1:2; VQL1:1, VCR and QN codelivery liposome with a ratio of 1:1; VQL1:2, VCR and QN codelivery liposome with a ratio of 1:2.
Mentions: An ideal liposome delivery system should be stable under physiological circulations but release the drug at the action site. The pH of blood is 7.4, and that of the intracellular microenvironment of tumor tissues is approximately 5.5.29 Therefore, the release of VCR and QN from FVCR, FQN, VCR liposomes, QN liposomes, L1:1, L1:2, VQL1:1, and VQL1:2 was examined in PBS of pH 7.4 and pH 5.5 at 37°C. As shown in Figure 4A and B, VCR liposomes and QN liposomes had a slower release rate than free VCR and free QN at pH 7.4, indicating that the liposome is capable of sustained drug release. When the pH of the release medium was decreased from 7.4 to 5.5, the release rate was more rapid for both drugs (Figure 4C and D). The cumulative drug release reached 70%–90% within the first 4 hours, suggesting that rapid drug release would occur as soon as the liposomes were endocytosed into the acidic endosomes of cancer cells. Furthermore, it was observed that QN was released a little faster than VCR at both pH values, which indicates that QN may reach the target site before VCR when they are coencapsulated in the same liposome.

Bottom Line: The antitumor effects of the formulation were also evaluated in multidrug-resistant tumor-bearing mice.The results of this in vivo study indicated that VQL could reverse VCR resistance.In addition, it reduced tumor volume 5.4-fold when compared with other test groups.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.

ABSTRACT
The use of vincristine (VCR) to treat cancer has been limited by its dose-dependent toxicity and development of drug resistance after repeated administrations. In this study, we investigated the mechanism by which quinine hydrochloride (QN) acts as a sensitizer for VCR. Our experiments used three kinds of multidrug-resistant cancer cells and demonstrated that QN worked by inducing intracellular depletion of adenosine triphosphate, increasing adenosine triphosphatase activity, and decreasing P-glycoprotein expression. Based on these results, we designed and prepared a VCR and QN codelivery liposome (VQL) and investigated the effect of coencapsulated QN on the in vitro cytotoxicity of VCR in cells and three-dimensional multicellular tumor spheroids. The antitumor effects of the formulation were also evaluated in multidrug-resistant tumor-bearing mice. The results of this in vivo study indicated that VQL could reverse VCR resistance. In addition, it reduced tumor volume 5.4-fold when compared with other test groups. The data suggest that VQL could be a promising nanoscaled therapeutic agent to overcome multidrug resistance, and may have important clinical implications for the treatment of cancer.

No MeSH data available.


Related in: MedlinePlus