Celastrol is a promising antitumor drug candidate, but the poor water solubility and cytotoxicity limit its clinical application. Herein, we synthesized a Celastrol (Cel)-chitosan oligosaccharide (CSO) conjugate (Cel-CSO) for drug delivery. Celastrol was conjugated to a CSO backbone via amide bond formation, which was verified by infrared spectrum (IR) analyses. The Cel-CSO contained ∼10 wt% of Celastrol showed excellent aqueous solubility (18.6 mg/mL) in comparation with the parent Celastrol. Cel-CSO significantly inhibited tumor growth, induced apoptosis, and effectively suppressed tumor metastasis in human pancreatic cancer cells (BxPC-3). While the cytotoxicity of Cel-CSO in hepatic cells (HL7702) was lower than that of the free Celastrol. Cel-CSO enhanced the anticancer efficacy, promoted the circulation time of Celastrol, and reduced the subacute toxicity, which indicated that CSO can be a promising Celastrol delivery system for pancreatic cancer therapy.

A new platform for triptolide (TP) delivery was prepared by conjugating TP to a carboxylmethyl chitosan (CMCS). Compared with the natural TP, the TP-conjugate (TP-CMCS) containing TP of ~5 wt% exhibited excellent aqueous solubility (>5 mg/mL). Results of in vitro experiments showed that TP-CMCS could relieve TP-induced inhibition on RAW264.7 cells and apoptosis, respectively. Compared with the TP group, TP-CMCS could effectively alleviate the toxicity injury of TP and decreased the mortality rate of the mice (p < 0.05). TP-CMCS did not cause much damage to the liver (AST and ALT) and kidney (BUN and CRE) (p < 0.05). After administration, the levels of IL-6, IL-1β, and TNF-α decreased, and the arthritis detumescence percentages increased significantly, and the bony erosion degree was distinctly decreased in the TP-CMCS groups and TP group. Our results suggested that TP-CMCS was a useful carrier for the treatment of RA, which enhanced aqueous solubility of free TP and reduced drug toxicity in vitro and in vivo.

A series of co-crystals of ascorbic acid were prepared with equimolar amounts of co-crystal formers (CCFs), including isonicotinic acid, nicotinic acid, 3,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid and m-hydroxybenzoic acid, by slow solvent evaporation and solvent-assisted grinding. The co-crystals were characterized by single-crystal X-ray diffraction spectroscopy, powder X-ray diffraction, IR spectroscopy, differential scanning calorimetry and thermogravimetric analysis. Molecular dynamics (MD) simulations further validated the interaction energy and the possible intermolecular hydrogen bonds among VC and CCFs. The co-crystals showed improved stability when exposed to different wavelengths of light, pH and temperatures compared to the free analogue, especially at higher pH (~9) and lower temperature (~4 °C).

Triptolide (TP) has its unique curative effect in the treatment of rheumatoid arthritis (RA), but its application is limited by the poor water solubility and multi-organ toxicity. We herein developed a novel nanoparticle platform composed of L-ascorbate palmitate (VP, vitamin C derivative) that can deliver TP to synergistically treat arthritis and inhibit the occurrence of oxidative stress. The TP-loaded nanoparticles (termed TP-VP NPs) showed the suitable particle size (about 145 nm) and good physical stability. TP-VP NPs effectively down-regulated IL-1β, IL-6 and TNF-α levels to inhibit the erosion of synovitis and bone tissue, and alleviate the swelling and deformation of CIA mice’s feet. Compared to the TP, TP-VP NPs could inhibit effectively the oxidative stress in liver, and alleviate significantly the triptolide-induced toxicity injury in liver, kidney and testicle. The results demonstrated that TP-VP NPs is a promising triptolide delivery system for the treatment of RA, which enhances the water solubility of TP and reduces the toxicity of TP in vivo.

Pancreatic cancer (PC), known as the ″king of cancer," is a prevalent and aggressive form of malignant tumor affecting the digestive tract. Triptolide (TP), an epoxidized diterpenoid lactone extracted from Tripterygium wilfordii, shows promising antitumor activity. However, the systemic toxicity and poor water solubility of TP inhibit its clinical application. In this work, Lycium barbarum polysaccharide (LBP)-modified selenium nanoparticles (SeNPs), capable of reducing severe toxicity and enhancing solubility, have been designed, synthesized, and applied for the treatment of PC. In vitro release results revealed that TP showed an acid-dependent and sustained-release effect. In Pan02 cells, the IC50 values of TP and LBP-SeNPs@TP were 26.03 ± 2.82 ng/mL and 11.80 ± 2.64 ng/mL, respectively. Similarly, the IC50 values of TP and LBP-SeNPs@TP for L02 cells were 15.76 ± 0.58 ng/mL and 32.73 ± 2.61 ng/mL, suggesting enhanced antitumor efficacy along with reduced toxicity. Flow cytometry analysis demonstrated that LBP-SeNPs@TP exerted the most potent apoptotic effect, achieving an early apoptosis rate of 24.5% and a late apoptosis rate of 45.3%. Notably, the mitochondrial membrane potential was significantly reduced, while ROS production was increased in the LBP-SeNPs@TP group. LBP-SeNPs@TP could significantly inhibit tumor growth while minimizing toxicity. RT-qPCR analysis demonstrated that LBP-SeNPs@TP upregulated the mRNA expression of Bax, Cyt C, and Caspase-3, while downregulating Bcl-2 expression in vitro and in vivo. The immunohistochemical analysis of the tumor tissue further confirmed these results. Overall, LBP-SeNPs emerge as a promising platform for poorly soluble drugs, offering a potential therapeutic approach for pancreatic cancer.

Celastrol (Cel) is a potential anticancer therapeutic candidate, but its limited practical applicability is due to its low solubility, poor tumor selectivity, and cytotoxicity. Clinically, ginsenoside Rg3 (RG3) is typically combined with chemotherapy to enhance antitumor effects and reduce side effects. Herein, we developed novel pH-sensitive prodrug nanoparticles (NPs) containing RG3 and Cel for the synergistic treatment of pancreatic cancer (PC). Amphiphilic prodrug, a PEGylated chitosan oligosaccharide coupled with RG3 via Schiff base bond, was self-assembled with hydrophobic Cel into NPs with drug loadings of 2.12% (Cel) and 1.63% (RG3). NPs exhibited a suitable particle size of 124.01 nm, zeta potential of -39.89 mV and good physical stability. In addition, NPs also showed a controlled drug release when the Schiff base bonds were hydrolyzed in the acidic environment. In Pan02 tumor-bearing mice, NPs exhibited a high accumulation in tumor tissues and prolonged blood circulation time. Furthermore, NPs could more effectively inhibit tumor growth and reduce systemic toxicity, compared with the free Cel, RG3, prodrug, and Cel + RG3. The results indicated that the NPs could provide a safe and promising nanoplatform for PC therapy.