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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

Chemical modification of hyaluronan (HA) to carboxymethyl hyaluronan (CMHA). HA was chemically modified to produce CMHA in a basic solution which modifies approximately 15–20% of the 6′-OH groups of the N-acetylglucosamine residues. This process reduces the molecular weight and introduces additional carboxyl groups for stabilization of nCaP.
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Related In: Results  -  Collection


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fig1: Chemical modification of hyaluronan (HA) to carboxymethyl hyaluronan (CMHA). HA was chemically modified to produce CMHA in a basic solution which modifies approximately 15–20% of the 6′-OH groups of the N-acetylglucosamine residues. This process reduces the molecular weight and introduces additional carboxyl groups for stabilization of nCaP.

Mentions: Utilizing HA as a targeting moiety to deliver chemotherapeutics to cancer cells has been an ongoing area of research. One approach has been to chemically modify HA to allow attachment of carboxyl-containing drugs [12], and an HA-Paclitaxel prodrug bioconjugate has been prepared that showed selective toxicity against cancer cells overexpressing CD44 [13, 14]. Drug carrier systems modified with HA have been shown to enter the cell via CD44 mediated endocytosis [15]. Chen et al. showed mesoporous silica nanoparticles targeted with HA entered cells expressing CD44 [16]. In this study targeted calcium phosphate nanoparticles (nCaP) were synthesized as the drug carrier. Calcium phosphate is an excellent biomaterial because it is biocompatible, resorbable, and nonimmunogenic [17–19]. CaP synthesized via wet precipitation will form microcrystals, instead of nanoparticles, if crystallization and agglomeration are not halted with a stabilizer. Limiting crystal growth and agglomeration with a stabilizer is important to improve injectability of colloidal suspensions of CaP used for drug delivery. In the present studies, chemically modified HA was evaluated as a dual stabilizer/targeting ligand for nCaP. The chemically modified HA had additional carboxylate groups installed on a predetermined fraction of the N-acetylglucosamine units at the 6-hydroxyl group [20, 21]. Carboxylates interact with and stabilize calcium ions during precipitation of CaP [22]. The structure of the carboxymethyl hyaluronan (CMHA) used for these studies is shown in Figure 1.


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)

Chemical modification of hyaluronan (HA) to carboxymethyl hyaluronan (CMHA). HA was chemically modified to produce CMHA in a basic solution which modifies approximately 15–20% of the 6′-OH groups of the N-acetylglucosamine residues. This process reduces the molecular weight and introduces additional carboxyl groups for stabilization of nCaP.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Chemical modification of hyaluronan (HA) to carboxymethyl hyaluronan (CMHA). HA was chemically modified to produce CMHA in a basic solution which modifies approximately 15–20% of the 6′-OH groups of the N-acetylglucosamine residues. This process reduces the molecular weight and introduces additional carboxyl groups for stabilization of nCaP.
Mentions: Utilizing HA as a targeting moiety to deliver chemotherapeutics to cancer cells has been an ongoing area of research. One approach has been to chemically modify HA to allow attachment of carboxyl-containing drugs [12], and an HA-Paclitaxel prodrug bioconjugate has been prepared that showed selective toxicity against cancer cells overexpressing CD44 [13, 14]. Drug carrier systems modified with HA have been shown to enter the cell via CD44 mediated endocytosis [15]. Chen et al. showed mesoporous silica nanoparticles targeted with HA entered cells expressing CD44 [16]. In this study targeted calcium phosphate nanoparticles (nCaP) were synthesized as the drug carrier. Calcium phosphate is an excellent biomaterial because it is biocompatible, resorbable, and nonimmunogenic [17–19]. CaP synthesized via wet precipitation will form microcrystals, instead of nanoparticles, if crystallization and agglomeration are not halted with a stabilizer. Limiting crystal growth and agglomeration with a stabilizer is important to improve injectability of colloidal suspensions of CaP used for drug delivery. In the present studies, chemically modified HA was evaluated as a dual stabilizer/targeting ligand for nCaP. The chemically modified HA had additional carboxylate groups installed on a predetermined fraction of the N-acetylglucosamine units at the 6-hydroxyl group [20, 21]. Carboxylates interact with and stabilize calcium ions during precipitation of CaP [22]. The structure of the carboxymethyl hyaluronan (CMHA) used for these studies is shown in Figure 1.

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