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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 vitro release testing of nCaPCMHACDDP using a modified USP Apparatus 4. Release was conducted in 10 mM PBS pH 7.4, 0.1% sodium azide at 37°C. The left axis is cumulative CDDP released with percent CDDP released on the right y-axis. The formulation provides sustained delivery of CDDP for 2 days under these infinite sink conditions. After 2 days nCaPCMHACDDP released 74% of the total CDDP bound. At day 7, nCaPCMHACDDP released an average of 86% of the total CDDP bound.
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fig3: In vitro release testing of nCaPCMHACDDP using a modified USP Apparatus 4. Release was conducted in 10 mM PBS pH 7.4, 0.1% sodium azide at 37°C. The left axis is cumulative CDDP released with percent CDDP released on the right y-axis. The formulation provides sustained delivery of CDDP for 2 days under these infinite sink conditions. After 2 days nCaPCMHACDDP released 74% of the total CDDP bound. At day 7, nCaPCMHACDDP released an average of 86% of the total CDDP bound.

Mentions: To design an effective nanoparticle drug delivery system it is essential to optimize the physicochemical interactions of each component: the carrier, the drug, and any biological targeting moiety [34]. It was shown in previous work that sodium polyacrylate (Darvan 811, D) halts CaP crystal growth [23]. This is due to the repeating carboxylate groups throughout the polymer. There is significant literature showing the carboxylate groups of sodium citrate (3 carboxylate groups per molecule) interact with the Ca ions during CaP precipitation acting as a surfactant to halt nucleation [22, 35–38]. Though these molecules effectively stabilize CaP, they have no biological targeting capacity. We therefore used a stabilizer that has biological targeting capability concurrent with nCaP stabilization. CMHA is a modified HA with additional carboxylate groups, thus allowing for more effective nCaP stabilization. CMHA at a degree of modification below 25% binds to HA binding proteins with comparable affinity and avidity as native HA. Importantly, cross-linked hydrogels based on thiolated CMHA improve wound healing in cutaneous and ophthalmic injuries [39], allow delivery of small molecules as well as growth factors and other macromolecules [40], and are safe and effective vehicles for cell delivery and retention [40]. Clinical products based on CMHA are in development for cell therapy [41]. Thus, CMHA was selected to enhance uptake of nCaPCMHACDDP by cells expressing CD44. After confirming that a stable calcium phosphate nanoparticle was achieved, we tested whether these nanoparticles could bind, release, and maintain biological efficacy of CDDP. The in vitro release of the nCaPCMHACDDP in PBS, pH 7.4, at 37°C over time can be seen in Figure 3. Under the rigorous, high speed and high volume release conditions nCaPCMHACDDP exhibited a burst release of 73% of the CDDP bound in two days which plateaued and reached a total of 86% after seven days.


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 vitro release testing of nCaPCMHACDDP using a modified USP Apparatus 4. Release was conducted in 10 mM PBS pH 7.4, 0.1% sodium azide at 37°C. The left axis is cumulative CDDP released with percent CDDP released on the right y-axis. The formulation provides sustained delivery of CDDP for 2 days under these infinite sink conditions. After 2 days nCaPCMHACDDP released 74% of the total CDDP bound. At day 7, nCaPCMHACDDP released an average of 86% of the total CDDP bound.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: In vitro release testing of nCaPCMHACDDP using a modified USP Apparatus 4. Release was conducted in 10 mM PBS pH 7.4, 0.1% sodium azide at 37°C. The left axis is cumulative CDDP released with percent CDDP released on the right y-axis. The formulation provides sustained delivery of CDDP for 2 days under these infinite sink conditions. After 2 days nCaPCMHACDDP released 74% of the total CDDP bound. At day 7, nCaPCMHACDDP released an average of 86% of the total CDDP bound.
Mentions: To design an effective nanoparticle drug delivery system it is essential to optimize the physicochemical interactions of each component: the carrier, the drug, and any biological targeting moiety [34]. It was shown in previous work that sodium polyacrylate (Darvan 811, D) halts CaP crystal growth [23]. This is due to the repeating carboxylate groups throughout the polymer. There is significant literature showing the carboxylate groups of sodium citrate (3 carboxylate groups per molecule) interact with the Ca ions during CaP precipitation acting as a surfactant to halt nucleation [22, 35–38]. Though these molecules effectively stabilize CaP, they have no biological targeting capacity. We therefore used a stabilizer that has biological targeting capability concurrent with nCaP stabilization. CMHA is a modified HA with additional carboxylate groups, thus allowing for more effective nCaP stabilization. CMHA at a degree of modification below 25% binds to HA binding proteins with comparable affinity and avidity as native HA. Importantly, cross-linked hydrogels based on thiolated CMHA improve wound healing in cutaneous and ophthalmic injuries [39], allow delivery of small molecules as well as growth factors and other macromolecules [40], and are safe and effective vehicles for cell delivery and retention [40]. Clinical products based on CMHA are in development for cell therapy [41]. Thus, CMHA was selected to enhance uptake of nCaPCMHACDDP by cells expressing CD44. After confirming that a stable calcium phosphate nanoparticle was achieved, we tested whether these nanoparticles could bind, release, and maintain biological efficacy of CDDP. The in vitro release of the nCaPCMHACDDP in PBS, pH 7.4, at 37°C over time can be seen in Figure 3. Under the rigorous, high speed and high volume release conditions nCaPCMHACDDP exhibited a burst release of 73% of the CDDP bound in two days which plateaued and reached a total of 86% after seven days.

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