In Vivo Anticancer Efficacy and Toxicity Studies of a Novel Polymer Conjugate N-Acetyl Glucosamine (NAG)–PEG–Doxorubicin for Targeted Cancer Therapy

Abstract

A novel polymer-drug conjugate, polyethylene glycol-N-(acetyl)-glucosamine-doxorubicin (PEG-NAG-DOX) was evaluated in this study for its in vivo potential for treatment of tumours demonstrating improved efficacy and reduced toxicity. The proposed polymer-drug conjugate comprised of polyethylene glycol-maleimide (mPEG-MAL, 30000 Da) as a carrier, doxorubicin (DOX) as an anticancer drug and N-acetyl glucosamine (NAG) as a targeting moiety as well as penetration enhancer. Doxorubicin has a potent and promising anticancer activity; however, severe cardiotoxicity limits its application in cancer treatment. By modifying DOX in PEG-NAG-DOX prodrug conjugate, we aimed to eliminate this limitation. In vivo anticancer efficacy of the conjugate was evaluated using BDF mice-induced skin melanoma model by i.v. administration of DOX conjugates. Anticancer efficacy studies were done by comparing tumour volume, body weight, organ index and percent survival rate of the animals. Tumour suppression achieved by PEG-NAG-DOX at the cumulative dose of 7.5 mg/kg was two-fold better than that achieved by DOX solution. Also, the survival rate for PEG-NAG-DOX conjugate was >70% as compared to <50% survival rate for DOX solution. In addition, toxicity studies and histopathological studies revealed that while maintaining its cytotoxicity towards tumour cells, PEG-NAG-DOX conjugate showed no toxicities to major organs. Therefore, PEG-NAG-DOX conjugate can be suggested as a desirable candidate for targeted cancer therapy.

A Novel Doxorubicin Prodrug with GRP78 Recognition and Nucleus-Targeting Ability for Safe and Effective Cancer Therapy

“…In addition, microscopic examination of the kidney sections indicated that DOX induced remarkable nephrotoxicity as demonstrated by tubular dilatation, glomerulus atrophy, and gathered nuclei (Figure 6). 36 It should be further noted that there were no pathological changes in the liver and kidney sections after NDP treatment because of its tumor-targeting ability.…”

Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

“…However, the expenses associated with the use of this species limit its application in large-scale molecular and/or therapeutic screening or modeling. To date, using a mouse model solely for drug screening (i.e., a single factor experimental study) is very rare, while multi-factorial experiments have often been performed, for example, simultaneous evaluation of antitumor efficacy and cardiotoxicity of cancer drugs, [395][396][397][398][399][400][401][402][403][404][405][406] and/or studies of cardioprotective strategies after using cancer drugs. [407][408][409][410][411][412] More importantly, many drugs, including oncologic pharmaceuticals, can often lead to cardiotoxic electrophysiological effects (e.g., QT prolongation, atrioventricular conduction blocks, and ventricular arrhythmias including torsades do pointes); thus, adverse electrophysiological effects represent important phenotypes of drug-induced cardiotoxicity.…”

Acceptor–donor–acceptor-type molecules with large electrostatic potential difference for effective NIR photothermal therapy

“…In the past few years, different NIR-II PTAs, including metal-organic frameworks, [18][19][20] gold nanostructures, 21,22 inorganic nanomagnets, 23 carbon nanotubes, 24,25 organic small molecules 26,27 and conjugated polymers, [28][29][30] were explored for applications in PTT. Particularly, benefiting from the development of nanotechnology, nanomaterials are widely exploited to boost the specificity of drugs to tumor tissues and simultaneously decrease the toxic effects on normal tissues, leading to improved therapeutic outcomes.…”