Tumor‑Anchoring Drug‑Loaded Fibrous Microspheres for MR Imaging‑Guided Local Chemotherapy and Metastasis Inhibition

Unobtrusive metastasis and invasion of malignant tumors are major causes for the death of cancer patients,and unfortunately the lack of specificity and abrupt release of anticancer drugs applied to the primary tumors are causing serious side effects in cancer management.Hence,the development of controlled local drug delivery systems that can effectively treat primary tumors and inhibit tumor metastasis is of critical importance for improved cancer therapeutics.Herein,we developed hyaluronic acid(HA)-modified porous fibrous microspheres as a drug delivery system with the functions of long-acting local chemotherapy,tumor metastasis inhibition and magnetic resonance(MR)imaging.Poly(lactic-co-glycolic acid)(PLGA)short fibers obtained by combined electrospinning and homogenization techniques were successfully modified with gadolinium(Gd^(3+))chelates and HA,which were subsequently mixed with doxorubicin(DOX)to obtain the multifunctional drug-loaded fibrous microspheres of DOX-PLGA-PEI-DTPA-Gd/HA(DOX−PGH)by electrospray and further crosslinking.The developed DOX−PGH microspheres with an average diameter of 118.8μm possess good structural stability and a high r1 relaxivity,and can achieve long-term DOX release.The cellular and animal experiments demonstrated that the DOX−PGH microspheres could facilitate targeted delivery of DOX to accelerate 4T1 cell death while reducing cancer cell metastasis due to the cooperative actions of long-term DOX-mediated chemotherapy and the fibrous microsphere-induced tumor anchoring to likely avoid primary tumor cell shedding,and render MR imaging of tumors during the treatment.The developed DOX−PGH microspheres may represent one of the updated local tumor chemotherapy formulations for improved tumor therapy with justified antitumor and anti-metastasis efficacy.