Multifunctional Core-Shell Glyconanoparticles for Galectin-3-Targeted, Trigger-Responsive Combination Chemotherapy.

Galectin-3 (gal-3) plays a crucial role in various cellular events associated to tumor metastasis and progression. In this direction, gal-3 binding core-shell glyconanoparticles based on citrus pectin (CP) have been designed for targeted, trigger-responsive combination drug delivery. Depolymerization via periodate oxidation in heterogeneous medium yielded low-molecular weight dialdehyde oligomers (CPDA) of CP with a gal-3 binding property (Kd = 160.90 µM). CPDA-based core-shell nanoparticles prepared to enhance the gal-3 binding specificity via a multivalent ligand presentation have shown to reduce homotypic cellular aggregation, tumor cell binding with endothelial cells, and endothelial tube formation, the major steps involved in the progression of cancer. Immune-fluorescence and flow cytometric analysis confirmed significant reduction in gal-3 expression on MDA-MB 231 cancer cells upon incubation with nanoparticles. An on-demand tumor microenvironment-responsive release of drugs at low pH and high concentrations of glucose and glutathione prevailing in tumor milieu was achieved by introducing a cleavable Schiff's base, a boronate ester, and disulfide linkages within the shell of the nanoparticles. Nanoparticles with encapsulated sulindac in the core and doxorubicin (DOX) in the shell demonstrated target specificity and enhanced internalization with synergistic cytotoxic effects with a 30-fold reduction in IC50 in DOX-resistant, triple-negative MDA-MB 231 breast cancer cells. Nanoparticles were radiolabeled with 131I radioisotopes with ≥80% efficiency while retaining its gal-3 binding property. Biodistribution studies of radiolabeled placebo nanoparticles and drug-loaded CPDA nanoparticles demonstrated proof of concept of gal-3 targeting seen as preferential accumulation in the gal-3-expressing tissues of the gastric tract. The CPDA core-shell nanoparticles are thus promising platforms for gal-3 targeting and inhibition of gal-3-mediated processes involved in cancer progression with a potential of radiolabeling for in vivo monitoring or delivering therapeutic doses of radiation and on-demand triggered, target-specific drug release.

Ultrasound-Responsive Carriers for Therapeutic Applications.

Ultrasound (US)-responsive carriers have emerged as promising theranostic candidates because of their ability to enhance US-contrast, promote image-guided drug delivery, cause on-demand pulsatile release of drugs in response to ultrasound stimuli, as well as to enhance the permeability of physiological barriers such as the stratum corneum, the vascular endothelium, and the blood-brain barrier (BBB). US-responsive carriers include microbubbles MBs, liposomes, droplets, hydrogels, and nanobubble-nanoparticle complexes and have been explored for cavitation-mediated US-responsive drug delivery. Recently, a transient increase in the permeability of the BBB by microbubble (MB)-assisted low-frequency US has shown promise in enhancing the delivery of therapeutic agents in the case of neurological disorders. Further, the periodic mechanical stimulus generated by US-responsive MBs have also been explored in tissue engineering and has directly influenced the differentiation of mesenchymal stem cells into cartilage. This Review discusses the various types of US-responsive carriers and explores their emerging roles in therapeutics ranging from drug delivery to tissue engineering.

Pro-apoptotic liposomes-nanobubble conjugate synergistic with paclitaxel: a platform for ultrasound responsive image-guided drug delivery.

Recently, liposomes-microbubble conjugates have emerged as a promising ultrasound (US)-responsive platform for cancer therapeutics. However, these are limited by their size in terms of tumor penetration. Additionally, there have been no attempts to enhance the smartness of such conjugates which have been used only as passive carriers. The present study explores submicron sized (756 ± 180.0 nm), US-responsive, phosphatidylserine (PS)-based paclitaxel-liposomes-nanobubble conjugates (PSPLBC) with an additional pro-apoptotic effect towards enhanced anti-cancer efficacy and image-guidance. The developed PSPLBC underwent cavitation in response to US-trigger, exhibiting in vitro pulsatile release with a 10-fold increase in cellular internalization as compared to control. The PS-containing formulations were found to be pro-apoptotic and exhibited strong synergism between PS and paclitaxel (Combination Index, CI < 0.1). This resulted in significantly high anti-tumor efficacy both in vitro and in vivo conditions (98.3 ± 0.8% tumor growth inhibition, TGI). Significant reduction in tumor proliferation index and MVD, as well as significant increase in apoptosis, were observed for the treated tumor sections. Further, the intravenous (i.v.) administration of PSPLBC enhanced the tumor US-contrast by 2-fold as compared to SonoVue. These results, show the potential of PSPLBC as a promising non-invasive, pro-apoptotic, smart DDS for US-responsive, image-guided cancer therapeutics.