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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

Efficacy study of nCaPCMHACDDP conducted on J:Nu mice bearing BT-474EMT tumors. Animals were treated once when their tumor volume reached 100 ± 10 mm3 and were compared to 2.8 mg/kg CDDP administered near the tumor. Tumor volume, grooming, and weight loss were monitored every other day following treatment. (a) The graph depicts average tumor volume (mm3) per group versus days posttreatment. The negative control saline IT (70 μL) had no effect on tumor growth. nCaPCMHA (60 μL) had no effect on tumor growth. CDDP at 2.8 mg/kg administered near the tumor delayed tumor growth. (b) Tumor weight at the end of the study or at time of euthanasia for the efficacy study shown in (a). Tumors were resected and weighed. Animals were euthanized if tumor diameter was measured > 2 cm or at the completion of the study (day 30). No significant differences were found between groups.
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fig9: Efficacy study of nCaPCMHACDDP conducted on J:Nu mice bearing BT-474EMT tumors. Animals were treated once when their tumor volume reached 100 ± 10 mm3 and were compared to 2.8 mg/kg CDDP administered near the tumor. Tumor volume, grooming, and weight loss were monitored every other day following treatment. (a) The graph depicts average tumor volume (mm3) per group versus days posttreatment. The negative control saline IT (70 μL) had no effect on tumor growth. nCaPCMHA (60 μL) had no effect on tumor growth. CDDP at 2.8 mg/kg administered near the tumor delayed tumor growth. (b) Tumor weight at the end of the study or at time of euthanasia for the efficacy study shown in (a). Tumors were resected and weighed. Animals were euthanized if tumor diameter was measured > 2 cm or at the completion of the study (day 30). No significant differences were found between groups.

Mentions: To assess the antitumor efficacy of the nCaPCMHACDDP, tumors were treated once by direct injection near the tumor with one of the following treatments: 2.8 mg/kg (60 μL) CDDP (8 mice), 60 μL of saline (4 mice), 60 μL of nCaPCMHA (4 mice), or 7 mg/kg nCaPCMHACDDP (8 mice), when tumor volume reached 100 ± 10 mm3. No significant differences in tumor volume or weights were found among groups (Figure 9(a)), even the positive control (CDDP only). No animal experienced weight loss greater than 2% at these doses (data not shown). At the time of euthanasia, tumors were resected and weighed to compare to volumetric measurements. The resulting tumor weights were plotted relative to treatment (Figure 9(b)). No significant differences were found between groups when analyzed according to tumor weight. No treatment caused toxicity to the animals as measured by weight loss and overall grooming/appearance. Survival over time posttreatment was evaluated for each group (Figure 10). Mice were not actually allowed to die due to the treatments or tumor growth; instead they were euthanized if the tumors reached a tumor length measurement greater than 20 mm. In this slow growing model half of the untreated animals still had small tumors at the end point of the study making it difficult to observe large changes in tumor size due to treatment. Large standard deviations of tumor volume in the untreated group (as well as treatment group) were another problem obscuring differences between groups. In our studies with the FaDu (human head and neck squamous cell carcinoma) tumor model, it was necessary to use a larger number of cells (2 × 106 cells) to achieve reproducible growth rather than 5 × 105 cells (which was used in these studies with the BT-474EMT). If a higher number of BT-474EMT cells were injected, limited variability in tumor volume might have occurred enabling a more discriminating evaluation of the test groups.


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)

Efficacy study of nCaPCMHACDDP conducted on J:Nu mice bearing BT-474EMT tumors. Animals were treated once when their tumor volume reached 100 ± 10 mm3 and were compared to 2.8 mg/kg CDDP administered near the tumor. Tumor volume, grooming, and weight loss were monitored every other day following treatment. (a) The graph depicts average tumor volume (mm3) per group versus days posttreatment. The negative control saline IT (70 μL) had no effect on tumor growth. nCaPCMHA (60 μL) had no effect on tumor growth. CDDP at 2.8 mg/kg administered near the tumor delayed tumor growth. (b) Tumor weight at the end of the study or at time of euthanasia for the efficacy study shown in (a). Tumors were resected and weighed. Animals were euthanized if tumor diameter was measured > 2 cm or at the completion of the study (day 30). No significant differences were found between groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig9: Efficacy study of nCaPCMHACDDP conducted on J:Nu mice bearing BT-474EMT tumors. Animals were treated once when their tumor volume reached 100 ± 10 mm3 and were compared to 2.8 mg/kg CDDP administered near the tumor. Tumor volume, grooming, and weight loss were monitored every other day following treatment. (a) The graph depicts average tumor volume (mm3) per group versus days posttreatment. The negative control saline IT (70 μL) had no effect on tumor growth. nCaPCMHA (60 μL) had no effect on tumor growth. CDDP at 2.8 mg/kg administered near the tumor delayed tumor growth. (b) Tumor weight at the end of the study or at time of euthanasia for the efficacy study shown in (a). Tumors were resected and weighed. Animals were euthanized if tumor diameter was measured > 2 cm or at the completion of the study (day 30). No significant differences were found between groups.
Mentions: To assess the antitumor efficacy of the nCaPCMHACDDP, tumors were treated once by direct injection near the tumor with one of the following treatments: 2.8 mg/kg (60 μL) CDDP (8 mice), 60 μL of saline (4 mice), 60 μL of nCaPCMHA (4 mice), or 7 mg/kg nCaPCMHACDDP (8 mice), when tumor volume reached 100 ± 10 mm3. No significant differences in tumor volume or weights were found among groups (Figure 9(a)), even the positive control (CDDP only). No animal experienced weight loss greater than 2% at these doses (data not shown). At the time of euthanasia, tumors were resected and weighed to compare to volumetric measurements. The resulting tumor weights were plotted relative to treatment (Figure 9(b)). No significant differences were found between groups when analyzed according to tumor weight. No treatment caused toxicity to the animals as measured by weight loss and overall grooming/appearance. Survival over time posttreatment was evaluated for each group (Figure 10). Mice were not actually allowed to die due to the treatments or tumor growth; instead they were euthanized if the tumors reached a tumor length measurement greater than 20 mm. In this slow growing model half of the untreated animals still had small tumors at the end point of the study making it difficult to observe large changes in tumor size due to treatment. Large standard deviations of tumor volume in the untreated group (as well as treatment group) were another problem obscuring differences between groups. In our studies with the FaDu (human head and neck squamous cell carcinoma) tumor model, it was necessary to use a larger number of cells (2 × 106 cells) to achieve reproducible growth rather than 5 × 105 cells (which was used in these studies with the BT-474EMT). If a higher number of BT-474EMT cells were injected, limited variability in tumor volume might have occurred enabling a more discriminating evaluation of the test groups.

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