Glycosaminoglycan-based injectable hydrogels with multi-functions in the alleviation of osteoarthritis.

Osteoarthritis (OA), as an "undead cancer", causes a serious burden for both individuals and society. In this study, a glycosaminoglycan-based injectable hydrogel was prepared with hyaluronic acid (HA), chondroitin sulfate E disaccharide (ΔUA-diSE) and thermosensitive Pluronic F127 (PF127) to provide a new strategy for OA alleviation. Both in vitro and in vivo biological evaluations were introduced to investigate the slow-release capacity, related mechanisms, and effectiveness of PF-HA-diSE on OA. The results demonstrated that PF-HA-diSE could alleviate OA effectively by regulating the complement system, especially the formation of C5b-9, and its downstream signals. Interestingly, we also found that PF127 was not only a drug carrier, but may have the potential on inhibiting C5b-9 formation. Altogether, these findings provided a more effective local drug delivery system for glycosaminoglycans in better treatment of OA and related diseases.

Combination of oxaliplatin and POM-1 by nanoliposomes to reprogram the tumor immune microenvironment.

Some chemotherapy can damage tumor cells, releasing damage-related molecular patterns including ATP to improve immunological recognition against the tumor by immunogenic cell death (ICD). However, the immune-stimulating ATP may be rapidly degraded into immunosuppressive adenosine by highly expressed CD39 and CD73 in the tumor microenvironment, which leads to immune escape. Based on the above paradox, a liposome nanoplatform combined with ICD inducer (oxaliplatin) and CD39 inhibitor (POM-1) is designed for immunochemotherapy. The liposomes efficiently load the phospholipid-like oxaliplatin prodrug, and the cationic charged surface could adsorb POM-1. Rationally designed DSPE-PEGn-pep, on the one hand, could cover and hide POM-1 to avoid systematic toxicity and, on the other, achieve a response and charge reversal to favor POM-1 shedding and tumor deep penetration. This combination maximizes the ICD effect, and takes two-pronged advantage of stimulating the immune response and relieving immune suppression. The designed POL can effectively inhibit the growth of in situ, lung metastasis and postoperative recurrence melanoma model and form long-term immune memory. With the powerful clinical transformation potential of nanoliposome platforms, this new synergistic strategy is expected to enhance anticancer effects safely and effectively.

Estimation of the critical quality attributes for hydroxypropyl methylcellulose with near-infrared spectroscopy and chemometrics.

With the implementation of quality by design (QbD), critical attributes of raw material (drug substance and excipients) are of significantly importance in pharmaceutical manufacturing process. It is desirable for the quality control of critical material attributes (CMAs) of excipients to ensure the quality of end product. This paper explored the feasibility of an at-line method for the quantitative analysis of hydroxypropoxy group in hydroxypropyl methylcellulose (HPMC) with near infrared spectroscopy (NIRS). Hydroxypropoxy group content can be seen as a CMA of HPMC for quality control. The partial least squares (PLS) model was built with 61 samples including 47 samples as calibration set, 14 samples as validation set by sample set partitioning based on joint x-y distances (SPXY) method. Multiplicative scattering correction (MSC) combined with Savitzkye-Golay (SG) smoothing with first derivative was used as the appropriate pretreatment method. Three variable selection methods including interval partial least-squares (iPLS), competitive adaptive reweighted Sampling (CARS), and the combination of the two methods (iPLS-CARS) were performed for optimizing the model. The results indicated that NIRS could predict rapidly and effectively the content of hydroxypropoxy group in HPMC. NIRS could be a potential method for the quality control of CMAs.

Determination of modification degree in BDDE-modified hyaluronic acid hydrogel by SEC/MS.

Determination of modification degree in BDDE-modified hyaluronic acid (HA) hydrogel is of particular interest. In this paper, three crosslinking parameters (degree of total modification, t-MOD; degree of cross-link modification, c-MOD; degree of pendent modification, p-MOD) are defined and determined by quantification of the modified fragments in hydrogel digestion by size exclusion chromatography combined with mass spectrometry (SEC-MS). The digestion products of a novel hyaluronidase HAase-B produced by Bacillus sp. A50 are studied and only a few modified fragments are identified by (1)H NMR and MS. As a result, Three HA hydrogels prepared in lab have different t-MOD, c-MOD and p-MOD, but the ratio of c-MOD to p-MOD result in the almost same value of 75%. Hydrogel products from Q-Med have nearly same t-MOD about 0.8% and c-MOD about 0.1%, the ratio of c-MOD to p-MOD is about 13%. Hydrogels from ANTEIS S.A all have much higher t-MOD values, the ratio of c-MOD and p-MOD is about 8%.