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Successful bone fragment fixation is a crucial factor in bone fracture healing, the fixation of crushed bone fragments could hinder bone fracture healing. Thus, ideal bone glues to effectively adhere and splice comminuted bone fragments are needed in clinical. Herein, an osteoinductive and biodegradable double cross-linked bone glue (GelMA-oDex-AMBGN) was constructed through Schiff's base reaction between commercial GelMA (with different substitution degrees of amino groups) and Odex mixed with amine-modified mesoporous bioactive glass nanoparticles (AMBGN), followed by crosslink with blue light irradiation. The GelMA-oDex-AMBGN bone glue successfully adhered and spliced the comminuted bone fragments of isolated rat skulls. GelMA-oDex-AMBGN promoted the proliferation of 3T3 cells and enhanced the expression of osteogenic proteins Runx2 and OCN in vitro. In rat cranial critical-sized defect models, GelMA-oDex-AMBGNs with different substitution degrees significantly increased the new bone contents at the fracture defect sites and promoted bone tissue regeneration in vivo. In conclusion, the double cross-linked bone glue (GelMA-oDex-AMBGN) was successfully constructed and can induce bone regeneration. Additionally, there was no significant difference in osteogenic activity among GelMA-oDex-AMBGNs with different substitution degrees and the equal content of AMBGN. [ABSTRACT FROM AUTHOR]

Micelles self-assembled from drug-conjugated polymers indicate advantages in alleviating the premature release before reaching the intended site. Hyaluronic acid (HA) is known to specifically bind with a transmembrane glycoprotein CD44, overexpressed in many types of cancerous cells, and can also be served as micelle carriers. However, an excess amount of drug conjugation to HA backbone may be detrimental to the receptor-mediated cellular uptake. Up to now, the effect of conjugation densities of drugs has never been determined on the physical properties and biological performance of resulting micelles. In the current study, camptothecin (CPT) was conjugated on HA through 3,3′-dithiodipropionic acid to self-assemble into reduction-sensitive micelles. The substitution degrees of CPT on HA backbone were tuned from around 4–20%, to clarify the effects on the cellular uptake efficiency and cytotoxicities of micelles, as well as the tumor accumulation and antitumor efficacy. The CPT substitution degree of around 15% on HA resulted in micelles with a higher cytotoxicity to 4T1 cells and achieved a better balance between the cellular uptake and reduction-triggered drug release, compared with other micelles. In contrast to a fast kidney clearance and an even distribution in major organs after intravenous injection of free CPT, the optimized micelles were accumulated in tumors, livers and lungs. The micelle content indicated a significant decrease in livers after 24 h, while that in tumors displayed a significant increase to 4.9% of the injection dose. The tumor accumulation of micelles led to strong tumor suppression with minimal systemic toxicity. The in situ tumor inhibition and the accumulation of micelles in liver and lungs inhibited tumor metastasis to these tissues. It demonstrates a feasible strategy to develop drug-HA conjugate micelles with a concise and tunable structure for tumor targeting and reduction-triggered release. Statement of Significance Hyaluronic acid (HA) can be served as micelle carriers and targeting ligands to tumor cells. However, the effects of drug conjugation densities on the physical profile and biological performance of resulting micelles have never been investigated. In the current study, camptothecin is conjugated on HA with reduction-sensitive linkers, and the substitution degrees of camptothecin on HA backbone vary from around 4–20%. The micelles with a substitution degree of around 15% achieve a better balance between the cellular uptake and reduction-triggered drug release and a higher cytotoxicity than others. It demonstrates a feasible strategy to develop drug-HA conjugate micelles with a concise and tunable structure for tumor targeting and reduction-triggered release. [ABSTRACT FROM AUTHOR]

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