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Block and random copolymers bearing cholic acid and oligo(ethylene glycol) pendant groups: aggregation, thermosensitivity, and drug loading.

Shao Y, Jia YG, Shi C, Luo J, Zhu XX - Biomacromolecules (2014)

Bottom Line: Based on in vitro drug release studies, 78% and 24% paclitaxel (PTX) were released in 24 h from micelles self-assembled by the block and random copolymers, respectively.PTX-loaded micelles formed by the block and random copolymers exhibited apparent antitumor efficacy toward the ovarian cancer cells with a particularly low half-maximal inhibitory concentration (IC50) of 27.4 and 40.2 ng/mL, respectively.Cholic acid-based micelles show promise as a versatile and potent platform for cancer chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Département de Chimie, Université de Montréal , C.P. 6128, Succ. Centre-ville, Montréal, Quebec H3C 3J7, Canada.

ABSTRACT
A series of block and random copolymers consisting of oligo(ethylene glycol) and cholic acid pendant groups were synthesized via ring-opening metathesis polymerization of their norbornene derivatives. These block and random copolymers were designed to have similar molecular weights and comonomer ratios; both types of copolymers showed thermosensitivity in aqueous solutions with similar cloud points. The copolymers self-assembled into micelles in water as shown by dynamic light scattering and transmission electron microscopy. The hydrodynamic diameter of the micelles formed by the block copolymer is much larger and exhibited a broad and gradual shrinkage from 20 to 54 °C below its cloud point, while the micelles formed by the random copolymers are smaller in size but exhibited some swelling in the same temperature range. Based on in vitro drug release studies, 78% and 24% paclitaxel (PTX) were released in 24 h from micelles self-assembled by the block and random copolymers, respectively. PTX-loaded micelles formed by the block and random copolymers exhibited apparent antitumor efficacy toward the ovarian cancer cells with a particularly low half-maximal inhibitory concentration (IC50) of 27.4 and 40.2 ng/mL, respectively. Cholic acid-based micelles show promise as a versatile and potent platform for cancer chemotherapy.

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Related in: MedlinePlus

(A) In vitro PTX release profiles from the micellesformed by the block copolymer PNOEG34-b-PNCA8 (circles) and the random copolymer P(NOEG-r-NCA)4:1 (squares) via dialysis against waterat room temperature (PTX: 1 g/L and polymer: 10 g/L). (B) Cytotoxicityof empty micelles and cancer cell killing activity of the free PTX(in 50% of Cremophor EL in dry ethanol) and PTX-loaded micelles formedby the block and random copolymers as a function of PTX concentration.All data are presented as the average ± standard deviation (n = 3).
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fig4: (A) In vitro PTX release profiles from the micellesformed by the block copolymer PNOEG34-b-PNCA8 (circles) and the random copolymer P(NOEG-r-NCA)4:1 (squares) via dialysis against waterat room temperature (PTX: 1 g/L and polymer: 10 g/L). (B) Cytotoxicityof empty micelles and cancer cell killing activity of the free PTX(in 50% of Cremophor EL in dry ethanol) and PTX-loaded micelles formedby the block and random copolymers as a function of PTX concentration.All data are presented as the average ± standard deviation (n = 3).

Mentions: PTX was loaded into micellesat a polymer concentration of 10.0 g/L and a theoretical drug loadingcontent (DLC) of 10.0 wt %. The micelles formed by PNOEG34-b-PNCA8 and P(NOEG-r-NCA)4:1 exhibited PTX loading efficiencies of 79.1% and88.8%, respectively (Table 3). Contrary toconventional thinking, after drug loading into the micellar core,the hydrodynamic diameter of resulting micelles actually showed asignificant decrease in size. This is intriguing but not unusual,and may be attributed to the tightening of the micelles caused bythe enhanced hydrophobic interaction between the drug and the micellecore.51In vitro drugrelease studies were carried out at room temperature with a dialysistube (MWCO 3500) in water. As shown in Figure 4A, 78% and 24% of PTX were released at the point of 24 h in the casesof PNOEG34-b-PNCA8 and P(NOEG-r-NCA)4:1, respectively. The release of PTX fromthe random copolymer-formed micelles was significantly slower thanfrom the block copolymer micelles at room temperature. This resultis quite interesting and even somewhat unusual, and may be attributableto the more densely assembled micellar structure of the random copolymerP(NOEG-r-NCA)4:1 at relatively low temperatures,as illustrated in Scheme 2.


Block and random copolymers bearing cholic acid and oligo(ethylene glycol) pendant groups: aggregation, thermosensitivity, and drug loading.

Shao Y, Jia YG, Shi C, Luo J, Zhu XX - Biomacromolecules (2014)

(A) In vitro PTX release profiles from the micellesformed by the block copolymer PNOEG34-b-PNCA8 (circles) and the random copolymer P(NOEG-r-NCA)4:1 (squares) via dialysis against waterat room temperature (PTX: 1 g/L and polymer: 10 g/L). (B) Cytotoxicityof empty micelles and cancer cell killing activity of the free PTX(in 50% of Cremophor EL in dry ethanol) and PTX-loaded micelles formedby the block and random copolymers as a function of PTX concentration.All data are presented as the average ± standard deviation (n = 3).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4020593&req=5

fig4: (A) In vitro PTX release profiles from the micellesformed by the block copolymer PNOEG34-b-PNCA8 (circles) and the random copolymer P(NOEG-r-NCA)4:1 (squares) via dialysis against waterat room temperature (PTX: 1 g/L and polymer: 10 g/L). (B) Cytotoxicityof empty micelles and cancer cell killing activity of the free PTX(in 50% of Cremophor EL in dry ethanol) and PTX-loaded micelles formedby the block and random copolymers as a function of PTX concentration.All data are presented as the average ± standard deviation (n = 3).
Mentions: PTX was loaded into micellesat a polymer concentration of 10.0 g/L and a theoretical drug loadingcontent (DLC) of 10.0 wt %. The micelles formed by PNOEG34-b-PNCA8 and P(NOEG-r-NCA)4:1 exhibited PTX loading efficiencies of 79.1% and88.8%, respectively (Table 3). Contrary toconventional thinking, after drug loading into the micellar core,the hydrodynamic diameter of resulting micelles actually showed asignificant decrease in size. This is intriguing but not unusual,and may be attributed to the tightening of the micelles caused bythe enhanced hydrophobic interaction between the drug and the micellecore.51In vitro drugrelease studies were carried out at room temperature with a dialysistube (MWCO 3500) in water. As shown in Figure 4A, 78% and 24% of PTX were released at the point of 24 h in the casesof PNOEG34-b-PNCA8 and P(NOEG-r-NCA)4:1, respectively. The release of PTX fromthe random copolymer-formed micelles was significantly slower thanfrom the block copolymer micelles at room temperature. This resultis quite interesting and even somewhat unusual, and may be attributableto the more densely assembled micellar structure of the random copolymerP(NOEG-r-NCA)4:1 at relatively low temperatures,as illustrated in Scheme 2.

Bottom Line: Based on in vitro drug release studies, 78% and 24% paclitaxel (PTX) were released in 24 h from micelles self-assembled by the block and random copolymers, respectively.PTX-loaded micelles formed by the block and random copolymers exhibited apparent antitumor efficacy toward the ovarian cancer cells with a particularly low half-maximal inhibitory concentration (IC50) of 27.4 and 40.2 ng/mL, respectively.Cholic acid-based micelles show promise as a versatile and potent platform for cancer chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Département de Chimie, Université de Montréal , C.P. 6128, Succ. Centre-ville, Montréal, Quebec H3C 3J7, Canada.

ABSTRACT
A series of block and random copolymers consisting of oligo(ethylene glycol) and cholic acid pendant groups were synthesized via ring-opening metathesis polymerization of their norbornene derivatives. These block and random copolymers were designed to have similar molecular weights and comonomer ratios; both types of copolymers showed thermosensitivity in aqueous solutions with similar cloud points. The copolymers self-assembled into micelles in water as shown by dynamic light scattering and transmission electron microscopy. The hydrodynamic diameter of the micelles formed by the block copolymer is much larger and exhibited a broad and gradual shrinkage from 20 to 54 °C below its cloud point, while the micelles formed by the random copolymers are smaller in size but exhibited some swelling in the same temperature range. Based on in vitro drug release studies, 78% and 24% paclitaxel (PTX) were released in 24 h from micelles self-assembled by the block and random copolymers, respectively. PTX-loaded micelles formed by the block and random copolymers exhibited apparent antitumor efficacy toward the ovarian cancer cells with a particularly low half-maximal inhibitory concentration (IC50) of 27.4 and 40.2 ng/mL, respectively. Cholic acid-based micelles show promise as a versatile and potent platform for cancer chemotherapy.

Show MeSH
Related in: MedlinePlus