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Tumor angiogenesis therapy using targeted delivery of Paclitaxel to the vasculature of breast cancer metastases.

Zhu S, Kisiel W, Lu YJ, Petersen LC, Ndungu JM, Moore TW, Parker ET, Sun A, Liotta DC, El-Rayes BF, Brat DJ, Snyder JP, Shoji M - J Drug Deliv (2014)

Bottom Line: The PTX-FFRck-fVIIa conjugate significantly reduces microvessel density in matrigel (p < 0.01-0.05) compared to PBS and unconjugated PTX.The conjugate significantly inhibits lung metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic carcinoma.In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective drug delivery and inhibiting angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Road, NE, Atlanta, GA 30322, USA.

ABSTRACT
Breast cancer aberrantly expresses tissue factor (TF) in cancer tissues and cancer vascular endothelial cells (VECs). TF plays a central role in cancer angiogenesis, growth, and metastasis and, as such, is a target for therapy and drug delivery. TF is the cognate receptor of factor VIIa (fVIIa). We have coupled PTX (paclitaxel, also named Taxol) with a tripeptide, phenylalanine-phenylalanine-arginine chloromethyl ketone (FFRck) and conjugated it with fVIIa. The key aim of the work is to evaluate the antiangiogenic effects of PTX-FFRck-fVIIa against a PTX-resistant breast cancer cell line. Matrigel mixed with VEGF and MDA-231 was injected subcutaneously into the flank of athymic nude mice. Animals were treated by tail vein injection of the PTX-FFRck-fVIIa conjugate, unconjugated PTX, or PBS. The PTX-FFRck-fVIIa conjugate significantly reduces microvessel density in matrigel (p < 0.01-0.05) compared to PBS and unconjugated PTX. The breast cancer lung metastasis model in athymic nude mice was developed by intravenous injection of MDA-231 cells expressing luciferase. Animals were similarly treated intravenously with the PTX-FFRck-fVIIa conjugate or PBS. The conjugate significantly inhibits lung metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic carcinoma. In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective drug delivery and inhibiting angiogenesis.

No MeSH data available.


Related in: MedlinePlus

Paclitaxel (PTX). (a) At left the locations of C2′OH and C7′OH are labeled; (b) at right, the C2′OH moiety has been coupled with a glutamic acid linker and the corresponding Phe-Phe-Arg tripeptide to give C2′-PTX-FFRck.
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sch1: Paclitaxel (PTX). (a) At left the locations of C2′OH and C7′OH are labeled; (b) at right, the C2′OH moiety has been coupled with a glutamic acid linker and the corresponding Phe-Phe-Arg tripeptide to give C2′-PTX-FFRck.

Mentions: The conjugation procedure is essentially the same as that described for conjugation of EF24 [24–27]. Briefly, C2′-PTX-FFRck in 100% DMSO was added dropwise to the fVIIa (MW 50,000) solution in a molar ratio of 3 : 1 at room temperature for 1-2 h while stirring, followed by gentle stirring at 4°C overnight. C7′-PTX-FFRck is less active than C2′-PTX-FFRck. C2′ and C7′ indicate the location of hydroxyl groups (OH) on PTX to which PTX-FFRck is conjugated and illustrated in Scheme 1 [23]. The unconjugated excess PTX-FFRck (FW: 1,500) was removed by exhaustive dialysis at 4°C using a dialysis membrane with a pore size of 13,000–15,000 MW to exclude molecules below 13,000 MW in 4 L of 10 mM Tris-HCl, pH 7.5, with several changes of the buffer every 12 h for several days to ensure all unbound PTX-FFRck is dialyzed out.


Tumor angiogenesis therapy using targeted delivery of Paclitaxel to the vasculature of breast cancer metastases.

Zhu S, Kisiel W, Lu YJ, Petersen LC, Ndungu JM, Moore TW, Parker ET, Sun A, Liotta DC, El-Rayes BF, Brat DJ, Snyder JP, Shoji M - J Drug Deliv (2014)

Paclitaxel (PTX). (a) At left the locations of C2′OH and C7′OH are labeled; (b) at right, the C2′OH moiety has been coupled with a glutamic acid linker and the corresponding Phe-Phe-Arg tripeptide to give C2′-PTX-FFRck.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4273585&req=5

sch1: Paclitaxel (PTX). (a) At left the locations of C2′OH and C7′OH are labeled; (b) at right, the C2′OH moiety has been coupled with a glutamic acid linker and the corresponding Phe-Phe-Arg tripeptide to give C2′-PTX-FFRck.
Mentions: The conjugation procedure is essentially the same as that described for conjugation of EF24 [24–27]. Briefly, C2′-PTX-FFRck in 100% DMSO was added dropwise to the fVIIa (MW 50,000) solution in a molar ratio of 3 : 1 at room temperature for 1-2 h while stirring, followed by gentle stirring at 4°C overnight. C7′-PTX-FFRck is less active than C2′-PTX-FFRck. C2′ and C7′ indicate the location of hydroxyl groups (OH) on PTX to which PTX-FFRck is conjugated and illustrated in Scheme 1 [23]. The unconjugated excess PTX-FFRck (FW: 1,500) was removed by exhaustive dialysis at 4°C using a dialysis membrane with a pore size of 13,000–15,000 MW to exclude molecules below 13,000 MW in 4 L of 10 mM Tris-HCl, pH 7.5, with several changes of the buffer every 12 h for several days to ensure all unbound PTX-FFRck is dialyzed out.

Bottom Line: The PTX-FFRck-fVIIa conjugate significantly reduces microvessel density in matrigel (p < 0.01-0.05) compared to PBS and unconjugated PTX.The conjugate significantly inhibits lung metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic carcinoma.In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective drug delivery and inhibiting angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Road, NE, Atlanta, GA 30322, USA.

ABSTRACT
Breast cancer aberrantly expresses tissue factor (TF) in cancer tissues and cancer vascular endothelial cells (VECs). TF plays a central role in cancer angiogenesis, growth, and metastasis and, as such, is a target for therapy and drug delivery. TF is the cognate receptor of factor VIIa (fVIIa). We have coupled PTX (paclitaxel, also named Taxol) with a tripeptide, phenylalanine-phenylalanine-arginine chloromethyl ketone (FFRck) and conjugated it with fVIIa. The key aim of the work is to evaluate the antiangiogenic effects of PTX-FFRck-fVIIa against a PTX-resistant breast cancer cell line. Matrigel mixed with VEGF and MDA-231 was injected subcutaneously into the flank of athymic nude mice. Animals were treated by tail vein injection of the PTX-FFRck-fVIIa conjugate, unconjugated PTX, or PBS. The PTX-FFRck-fVIIa conjugate significantly reduces microvessel density in matrigel (p < 0.01-0.05) compared to PBS and unconjugated PTX. The breast cancer lung metastasis model in athymic nude mice was developed by intravenous injection of MDA-231 cells expressing luciferase. Animals were similarly treated intravenously with the PTX-FFRck-fVIIa conjugate or PBS. The conjugate significantly inhibits lung metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic carcinoma. In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective drug delivery and inhibiting angiogenesis.

No MeSH data available.


Related in: MedlinePlus