Galactoxyloglucan-Modified Nanocarriers of Doxorubicin for Improved Tumor-Targeted Drug Delivery with Minimal Toxicity

Abstract

Doxorubicin (Dox) is commonly used to treat human malignancies, and the efficacy of Dox can be maximized by limiting toxicity when combined with nanoparticles. PST-Dox nanoparticles were prepared via conjugation of doxorubicin to galactoxyloglucan polysaccharide (PST001) isolated from Tamarindus indica (Ti), and by ionic gelation with tripolyphosphate (TPP). This formulation possessed superior therapeutic efficiency because of the small size and increased surface-tovolume ratio. The PST-Dox nanoparticles exhibited a pH-responsive Dox release in the acidic pH of 4.5, favoring as high as 90% Dox release in a sustainable manner. PST-Dox was characterized and evaluated for its in vitro and in vivo anticancer effects. Surprisingly, this nanoparticle formulation retained the cytotoxic effects of PST001 even at lower concentrations. In vitro studies confirmed the selective cytotoxicity of PST-Dox in cancer cells through the induction of apoptosis. In vivo toxicity studies demonstrated a lower LD50 for Dox and a higher LD50 for the PST-Dox. Evaluation of the biochemical, hematological and histopathological parameters in mice supported the safety and efficacy of this formulation compared to Dox. Biodistribution data substantiated the tumor-specific delivery of these particles. Although prospective studies are warranted, in a complex disease such as cancer, cell-selective and pH-sensitive nanoparticle-based targeted drug delivery systems should be used as an effective choice over standard agents, such as doxorubicin.

Anticancer activity of galactoxyloglucan polysaccharide-conjugated doxorubicin nanoparticles: Mechanistic insights and interactome analysis

“…Spectral analysis indicated that PST001 retained its identity, even after combining with the drug moiety Dox, and there occurred inter-molecular interactions between PST001 and Dox during the formation of the PST-Dox nanoparticles. The FTIR spectra obtained was similar to what we recently published [19], indicating there were no significant variations even on long-term storage (Supplementary Fig. 1).…”

“…1G). Our published studies demonstrated that PST-Dox nanoparticles (10 nm) had a Dox encapsulation efficiency of 70% [19]. The high Dox content in the nanoparticles may in turn increase the efficiency of the treatment at the targeted sites.…”

“…Carbohydrate content was determined colorimetrically by phenol-sulfuric acid method of Dubois [20]. PST-Dox nanoparticles were prepared by the process of ionic gelation, using sodium tripolyphosphate (TPP) as published earlier [19]. The nanoparticles were characterized for quantitative measures of particle size by transmission electron microscopy (TEM) at an accelerated voltage of 80 kV (Hitachi TEM system).…”

“…Dox encapsulation with PST001 by the process of ionic gelation produced PST-Dox nanoparticles that possessed superior therapeutic efficiency, due to their smaller size and increased surface-to-volume ratio. The PST-Dox conjugated nanoparticles exhibited excellent in vitro cytotoxicity, pH-responsive Dox release, tumor specific bio-distribution and a higher LD 50 in mice compared to parental Dox [19].…”

Easy on-demand self-assembly of lateral nanodimensional hybrid graphene oxide flakes for near-infrared-induced chemothermal therapy

“…The results for the free DOX group could be related to the previously reported toxicities that cause weight loss in mice, such as cardiotoxicity, neurotoxicity and nephrotoxicity. [45][46][47] Unlike the control and free DOX groups, the enhanced anticancer effects and reduced toxicities from application of the nGO@DOX-cPEG flakes (Supplementary Figure S8) led to accumulation and efficient delivery of DOX to tumor sites, which may be due to the sustained release and prolonged circulation in the bloodstream and the enhanced permeation and retention effect. 47,48 In addition, histopathological and immunohistochemical analyses were performed on the tumor masses to determine the expression levels of caspase-3, PARP, CD31 and Ki-67 (Figure 7c; Supplementary Table S2).…”