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Carboxymethyl Hyaluronan-Stabilized Nanoparticles for Anticancer Drug Delivery.

Woodman JL, Suh MS, Zhang J, Kondaveeti Y, Burgess DJ, White BA, Prestwich GD, Kuhn LT - Int J Cell Biol (2015)

Bottom Line: CMHA stabilized particles (nCaP(CMHA)) were loaded with the chemotherapy drug cis-diamminedichloroplatinum(II) (CDDP) to form nCaP(CMHA)CDDP. nCaP(CMHA)CDDP was determined to be poorly crystalline hydroxyapatite, 200 nm in diameter with a -43 mV zeta potential. nCaP(CMHA)CDDP exhibited a two-day burst release of CDDP that tapered resulting in 86% release by 7 days.Subcutaneous BT-474EMT tumors were more reproducibly inhibited by a near tumor dose of 2.8 mg/kg CDDP than a 7 mg/kg dose nCaP(CMHA)CDDP.This was likely due to a lack of distribution of nCaP(CMHA)CDDP throughout the dense tumor tissue that limited drug diffusion.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials Science and Engineering, University of Connecticut, Storrs, CT 06269, USA ; Department of Reconstructive Sciences, UConn Health, Farmington, CT 06030, USA.

ABSTRACT
Carboxymethyl hyaluronic acid (CMHA) is a semisynthetic derivative of HA that is recognized by HA binding proteins but contains an additional carboxylic acid on some of the 6-hydroxyl groups of the N-acetyl glucosamine sugar units. These studies tested the ability of CMHA to stabilize the formation of calcium phosphate nanoparticles and evaluated their potential to target therapy resistant, CD44(+)/CD24(-/low) human breast cancer cells (BT-474EMT). CMHA stabilized particles (nCaP(CMHA)) were loaded with the chemotherapy drug cis-diamminedichloroplatinum(II) (CDDP) to form nCaP(CMHA)CDDP. nCaP(CMHA)CDDP was determined to be poorly crystalline hydroxyapatite, 200 nm in diameter with a -43 mV zeta potential. nCaP(CMHA)CDDP exhibited a two-day burst release of CDDP that tapered resulting in 86% release by 7 days. Surface plasmon resonance showed that nCaP(CMHA)CDDP binds to CD44, but less effectively than CMHA or hyaluronan. nCaP(CMHA-AF488) was taken up by CD44(+)/CD24(-) BT-474EMT breast cancer cells within 18 hours. nCaP(CMHA)CDDP was as cytotoxic as free CDDP against the BT-474EMT cells. Subcutaneous BT-474EMT tumors were more reproducibly inhibited by a near tumor dose of 2.8 mg/kg CDDP than a 7 mg/kg dose nCaP(CMHA)CDDP. This was likely due to a lack of distribution of nCaP(CMHA)CDDP throughout the dense tumor tissue that limited drug diffusion.

No MeSH data available.


Related in: MedlinePlus

In vivo tumor take rate and maximum tolerable dose studies. (a) Tumor take rate study performed in athymic nude mice with 5 × 105 BT-474EMT cells injected subcutaneously in right rear flank of animals. Data represents average tumor volume versus days following inoculation with standard deviations. (b) Maximum tolerable dose study conducted with athymic nude mice (6–8 weeks old) carrying BT-474EMT tumors. An intratumoral 7 mg/kg dose of nCaPCMHACDDP (4 mice/group) was compared to an untreated control (4 mice/group). nCaPCMHACDDP caused minimal weight loss at 7 mg/kg and all animals recovered.
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fig8: In vivo tumor take rate and maximum tolerable dose studies. (a) Tumor take rate study performed in athymic nude mice with 5 × 105 BT-474EMT cells injected subcutaneously in right rear flank of animals. Data represents average tumor volume versus days following inoculation with standard deviations. (b) Maximum tolerable dose study conducted with athymic nude mice (6–8 weeks old) carrying BT-474EMT tumors. An intratumoral 7 mg/kg dose of nCaPCMHACDDP (4 mice/group) was compared to an untreated control (4 mice/group). nCaPCMHACDDP caused minimal weight loss at 7 mg/kg and all animals recovered.

Mentions: Importantly, the nCaPCMHACDDP had equivalent cytotoxicity to CDDP in vitro which means nCaPCMHA had no negative impact on the biological activity of CDDP and thus these particles were suitable candidates for evaluation in an in vivo tumor model. The in vivo tumor forming capability of BT-474EMT cells had not been previously studied; therefore, their ability to form tumors was first examined in a tumor take rate study. BT-474EMT tumors formed after cell injections were 50 mm3 on average after 7 days. After approximately 12 days tumors were 100 mm3 (Figure 8(a)). Animals were monitored for 25 days following inoculation where tumors continued to grow steadily up to 500 mm3 without necrosis. The comparable mesenchymal-derived human MCF-7 human BC cells were also tested under the same conditions in an in vivo tumor model and were found to have similar growth rates as the BT-474EMT with volumes reaching 500 ± 100 mm3 at 20 days following inoculation [30]. These studies confirmed that this new human breast cancer tumor model BT-474EMT was not too fast growing and did not develop necrotic tumors.


Carboxymethyl Hyaluronan-Stabilized Nanoparticles for Anticancer Drug Delivery.

Woodman JL, Suh MS, Zhang J, Kondaveeti Y, Burgess DJ, White BA, Prestwich GD, Kuhn LT - Int J Cell Biol (2015)

In vivo tumor take rate and maximum tolerable dose studies. (a) Tumor take rate study performed in athymic nude mice with 5 × 105 BT-474EMT cells injected subcutaneously in right rear flank of animals. Data represents average tumor volume versus days following inoculation with standard deviations. (b) Maximum tolerable dose study conducted with athymic nude mice (6–8 weeks old) carrying BT-474EMT tumors. An intratumoral 7 mg/kg dose of nCaPCMHACDDP (4 mice/group) was compared to an untreated control (4 mice/group). nCaPCMHACDDP caused minimal weight loss at 7 mg/kg and all animals recovered.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4581577&req=5

fig8: In vivo tumor take rate and maximum tolerable dose studies. (a) Tumor take rate study performed in athymic nude mice with 5 × 105 BT-474EMT cells injected subcutaneously in right rear flank of animals. Data represents average tumor volume versus days following inoculation with standard deviations. (b) Maximum tolerable dose study conducted with athymic nude mice (6–8 weeks old) carrying BT-474EMT tumors. An intratumoral 7 mg/kg dose of nCaPCMHACDDP (4 mice/group) was compared to an untreated control (4 mice/group). nCaPCMHACDDP caused minimal weight loss at 7 mg/kg and all animals recovered.
Mentions: Importantly, the nCaPCMHACDDP had equivalent cytotoxicity to CDDP in vitro which means nCaPCMHA had no negative impact on the biological activity of CDDP and thus these particles were suitable candidates for evaluation in an in vivo tumor model. The in vivo tumor forming capability of BT-474EMT cells had not been previously studied; therefore, their ability to form tumors was first examined in a tumor take rate study. BT-474EMT tumors formed after cell injections were 50 mm3 on average after 7 days. After approximately 12 days tumors were 100 mm3 (Figure 8(a)). Animals were monitored for 25 days following inoculation where tumors continued to grow steadily up to 500 mm3 without necrosis. The comparable mesenchymal-derived human MCF-7 human BC cells were also tested under the same conditions in an in vivo tumor model and were found to have similar growth rates as the BT-474EMT with volumes reaching 500 ± 100 mm3 at 20 days following inoculation [30]. These studies confirmed that this new human breast cancer tumor model BT-474EMT was not too fast growing and did not develop necrotic tumors.

Bottom Line: CMHA stabilized particles (nCaP(CMHA)) were loaded with the chemotherapy drug cis-diamminedichloroplatinum(II) (CDDP) to form nCaP(CMHA)CDDP. nCaP(CMHA)CDDP was determined to be poorly crystalline hydroxyapatite, 200 nm in diameter with a -43 mV zeta potential. nCaP(CMHA)CDDP exhibited a two-day burst release of CDDP that tapered resulting in 86% release by 7 days.Subcutaneous BT-474EMT tumors were more reproducibly inhibited by a near tumor dose of 2.8 mg/kg CDDP than a 7 mg/kg dose nCaP(CMHA)CDDP.This was likely due to a lack of distribution of nCaP(CMHA)CDDP throughout the dense tumor tissue that limited drug diffusion.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials Science and Engineering, University of Connecticut, Storrs, CT 06269, USA ; Department of Reconstructive Sciences, UConn Health, Farmington, CT 06030, USA.

ABSTRACT
Carboxymethyl hyaluronic acid (CMHA) is a semisynthetic derivative of HA that is recognized by HA binding proteins but contains an additional carboxylic acid on some of the 6-hydroxyl groups of the N-acetyl glucosamine sugar units. These studies tested the ability of CMHA to stabilize the formation of calcium phosphate nanoparticles and evaluated their potential to target therapy resistant, CD44(+)/CD24(-/low) human breast cancer cells (BT-474EMT). CMHA stabilized particles (nCaP(CMHA)) were loaded with the chemotherapy drug cis-diamminedichloroplatinum(II) (CDDP) to form nCaP(CMHA)CDDP. nCaP(CMHA)CDDP was determined to be poorly crystalline hydroxyapatite, 200 nm in diameter with a -43 mV zeta potential. nCaP(CMHA)CDDP exhibited a two-day burst release of CDDP that tapered resulting in 86% release by 7 days. Surface plasmon resonance showed that nCaP(CMHA)CDDP binds to CD44, but less effectively than CMHA or hyaluronan. nCaP(CMHA-AF488) was taken up by CD44(+)/CD24(-) BT-474EMT breast cancer cells within 18 hours. nCaP(CMHA)CDDP was as cytotoxic as free CDDP against the BT-474EMT cells. Subcutaneous BT-474EMT tumors were more reproducibly inhibited by a near tumor dose of 2.8 mg/kg CDDP than a 7 mg/kg dose nCaP(CMHA)CDDP. This was likely due to a lack of distribution of nCaP(CMHA)CDDP throughout the dense tumor tissue that limited drug diffusion.

No MeSH data available.


Related in: MedlinePlus