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A multiple drug loaded, functionalized pH-sensitive nanocarrier as therapeutic and epigenetic modulator for osteosarcoma.

ABSTRACT: Osteosarcoma is a malignant condition affecting adolescents and children more than adults. Nanobiomedicine has opened up several avenues which have increased therapeutic efficiencies than the conventional treatment for the same. In the current study, a novel organic nanoparticle was devised conjugated with bisphosphonate zoledronic acid which has an affinity for bone tissues. Moreover, the nanoparticle was loaded with multiple anti-cancer drugs like gemcitabine and epirubicin. The nanoparticles were characterized by microscopic analysis, entrapment and loading efficiencies, bone affinity studies, in-vitro release studies, cytotoxicity studies and finally in-vivo tumor regression studies. Bone affinity studies depicted a high affinity of zoledronic acid towards bone powder. The nanoparticle exhibited a nanosize dimension, high entrapment and loading efficiencies with uniform symmetry devoid of agglomeration. The in-vitro release experiments showed a measured release of drugs over a longer time without any hint of burst release. However, the release was comparatively for a longer duration in acidic pH and normal physiological pH which may be excellent for therapeutic efficiency. The cytotoxicity studies revealed enhanced cytotoxic effect for MG-63 cell lines in comparison of free drug or single drug combinations. Nonetheless, they proved to be cytocompatible with primary bone cells. Additionally, cellular uptake of nanoparticle was appreciably improved. Significant tumor (250%) regression was seen upon treatment with multiple drug loaded zoledronic acid conjugated nanoparticle, along with epigenetic changes affecting microRNA expressions. The increased cytotoxicity and increased cellular uptake may be of greater advantage in systemic osteosarcoma therapy. Combining all results, our study demonstrated substantial potential towards management of osteosarcoma.

SUBMITTER: Yuan Y

PROVIDER: S-EPMC7511925 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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A multiple drug loaded, functionalized pH-sensitive nanocarrier as therapeutic and epigenetic modulator for osteosarcoma.

Yuan Ye Y Song Jia-Xing JX Zhang Mei-Na MN Yuan Bao-Shan BS

Scientific reports 20200923 1

Osteosarcoma is a malignant condition affecting adolescents and children more than adults. Nanobiomedicine has opened up several avenues which have increased therapeutic efficiencies than the conventional treatment for the same. In the current study, a novel organic nanoparticle was devised conjugated with bisphosphonate zoledronic acid which has an affinity for bone tissues. Moreover, the nanoparticle was loaded with multiple anti-cancer drugs like gemcitabine and epirubicin. The nanoparticles ...[more]

PMID: 32968136

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Project description:BackgroundBased on the concept of "multimodal analgesia", a novel dual drug delivery system was designed to achieve synergistic analgesia between najanajaatra venom protein (αCT) and resveratrol (Res). In order to meet the joint loading of two drugs with different physicochemical properties without affecting each other, an oral Janus nanoparticle (JNP) with a unique cavity structure and synergistic drug delivery was constructed using an improved double emulsion solvent evaporation method, and combined with low-molecular-weight chitosan/sodium alginate and PLGA to achieve its pH-responsive.ResultsThe synthesized αCT/Res-JNPs are homogeneous in shape, with a two-compartment structure, approximately 230 nm in size, and zeta potential of 23.6 mV. Drug release assayed in vitro show that JNP was stable in simulated gastric juice (pH = 1.2) but was released in phosphate buffer saline (pH = 7.4). After intragastric administration in rats, PK evaluation showed that αCT/Res-JNPs could significantly improve the oral bioavailability, and the simultaneous encapsulation of the two drugs had no significant interaction on PK parameters. An obvious synergistic analgesic effects of αCT/Res-JNPs was confirmed in a spinal cord injury and acute pain model. Confocal laser scanning microscopy and single-pass intestinal perfusion model provided strong evidence that αCT/Res-JNPs could pass through intestinal epithelial cells, and the endocytosis pathway was mainly involved in the mediation and pinocytosis of reticulin. The concentrations of αCT and Res from αCT/Res-JNP in lymphatic transport were only about 8.72% and 6.08% of their blood concentrations at 1 h, respectively, which indicated that lymphatic transport in the form of JNP has limited advantages in improving the oral bioavailability of Res and αCT. Cellular uptake efficiency at 4 h was about 10-15% in Caco-2 cell lines for αCT/Res-JNP, but was reduced to 7% in Caco-2/HT29-MTX co-culture models due to the hindrance by the mucus layers. Approximately 12-17% of αCT/Res-JNP were transported across Caco-2/HT29-MTX/Raji monolayers. The cumulative absorption of JNP in three cell models was higher than that of free drug.ConclusionsThis study investigated the contribution of Janus nanoparticles in oral absorption, and provide a new perspective for oral administration and analgesic treatment of dual drug delivery system containing peptide drugs.

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A multiple drug loaded, functionalized pH-sensitive nanocarrier as therapeutic and epigenetic modulator for osteosarcoma.

Publications

A multiple drug loaded, functionalized pH-sensitive nanocarrier as therapeutic and epigenetic modulator for osteosarcoma.

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