Abstract
The complex construction within the oral cavity causes incomplete surgical resection of oral squamous cell carcinoma (OSCC) that may enhance the risk of recurrence and metastasis in the treatment. In situ forming injectable hydrogels with minimally invasive procedures, encapsulation stability and stimuli-responsive degradation have emerged as promising carriers for local drug delivery. In this study, doxorubicin (DOX) was first encapsulated in biodegradable poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA) micelles and then loaded into an in situ injectable hyaluronic acid (HA) hydrogel, which was cross-linked by a matrix metalloproteinase-2 (MMP-2)-responsive peptide (GCRDGPQGIWGQDRCG) through a Michael addition reaction. In vitro studies demonstrated that the HA hydrogel had a sensitive MMP-2-responsive drug release profile. Investigations including MTT, live-dead, apoptosis, and wound healing assays illustrated that DOX micelle-loaded HA hydrogels exhibited outstanding cytotoxicity against squamous carcinoma cells (SCC-15). Furthermore, by in vivo studies, we also proved that HA hydrogels degraded faster in the tumor site than in normal tissue, which led to a local sustained release of DOX-loaded micelles and tumor growth inhibition of oral squamous cell carcinoma (OSCC) without any damage to the organs. Therefore, this work provides a remarkable drug delivery platform for local chemotherapy and other applications.
Highlights
Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck,[1] and it is the sixth leading cancer by incidence worldwide with approximately 600 000 new cases reported annually.[2,3,4] unceasing progress in clinical cancer treatments has been made in recent years, the 5 year survival rate of oral squamous cell carcinoma (OSCC) hovers at approximately 50%.4,5 Anatomically, there are many anatomic subsites in the oral cavity, including the labial mucosa, buccal mucosa, oor of the mouth, alveolar ridge and gingiva, anterior two-thirds of the tongue, hard palate, and retromolar trigone.[1]
By in vivo studies, we proved that hyaluronic acid (HA) hydrogels degraded faster in the tumor site than in normal tissue, which led to a local sustained release of DOX-loaded micelles and tumor growth inhibition of oral squamous cell carcinoma (OSCC) without any damage to the organs
We developed a matrix metalloproteinase-2 (MMP-2)-responsive in situ forming injectable hyaluronic acid (HA) hydrogel, which was used as the depot of doxorubicin (DOX)-encapsulated biodegradable micelles for the local chemotherapy of OSCC
Summary
In situ forming injectable hydrogels with minimally invasive procedures, high biocompatibility and desirable bioactivity have been widely developed for drug delivery and tissue engineering applications.[6,7,8,9,10] The encapsulation of the therapeutic drugs into the hydrogel depots for the treatment of local disease has many attractive advantages.[11,12,13] by molecular design and manipulation of the preparation parameters, such as the content and cross-linking density, the drug release behavior from hydrogel depots can be signi cantly controlled for improving the drug bioavailability, action time and unanticipated adverse effects. A variety of stimuliresponsive factors such as acidity,[14] light,[15] magnetism,[16] temperature,[17] and enzymes,[18] can be utilized to design and fabricate smart hydrogel materials for local sustained drug release aimed at achieving the optimal therapeutic efficacy while reducing the side-effects of drugs Among those stimuli-responsive factors, speci c enzymes have attracted enormous attention due to their striking and robust characteristics.[19] enzyme-responsive drug release systems have been extensively explored for the treatment of various diseases, especially for cancer.[20] Matrix metalloproteinase[2] (MMP-2) is overexpressed in many types of cancer including OSCC, and it has been reported that MMP-2 plays a key role in cancer invasion, progression, recurrence and metastasis.[21] The peptide GPQGIWGQ is one of its known substrates, which can be selectively cleaved by MMP-2.22–26 incorporating GPQGIWGQ into a cross-linked structure may endow hydrogels with MMP-2responsive degradability that is suitable for fabricating local stimuli-responsive drug release systems for tumor treatment and the prevention of recurrence.[27,28,29,30,31]. The in vivo investigations proved that hydrogel depot can effectively degrade and release the loaded NanoDOX in the tumor site, and it strongly inhibited the tumor growth of OSCC as well as reduced the side effects of drugs
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