Conventional chemotherapeutic agents are limited by their lack of targeting and penetration and their short retention time, and chemotherapy might induce an immune suppressive environment. Peptide self-assembly can result in a specific morphology, and the resulting morphological changes are stimuli responsive to the external environment, which is important for drug permeation and retention of encapsulated chemotherapeutic agents. In this study, a polypeptide (Pep1) containing the peptide sequences PLGLAG and RGD that is responsive to matrix metalloproteinase 2 (MMP-2) was successfully developed. Pep1 underwent a morphological transformation from a spherical structure to aggregates with a high aspect ratio in response to MMP-2 induction. This drug delivery system (DI/Pep1) can transport doxorubicin (DOX) and indomethacin (IND) simultaneously to target tumor cells for subsequent drug release while extending drug retention within tumor cells, which increases immunogenic cell death and facilitates the immunotherapeutic effect of CD4 + T cells. Ultimately, DI/Pep1 attenuated tumor-associated inflammation, enhanced the body's immune response, and inhibited breast cancer growth by combining the actions of DOX and IND. Our research offers an approach to hopefully enhance the effectiveness of cancer treatment.
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.
7-Ethyl-10-hydroxycamptothecin (SN-38)-loaded polyethylene glycol-GPLGVRG-poly β-benzyl- l -aspartic acid (PEG-GPLGVRG-PBLA) self-assemblies were successfully prepared using a classical nanoprecipitation method to give an enzyme-responsive nano-drug delivery system. The PEG-GPLGVRG-PBLA/SN-38 self-assemblies were characterized by transmission electron microscopy , dynamic light scattering , and high-performance liquid chromatography. The encapsulation efficiency was 91.7 ± 1.21% and the drug loading was 16.6 ± 0.93%. The 12 h in vitro release of SN-38 from PEG-GPLGVRG-PBLA/SN-38 treated with MMP-2 was 73.2 ± 2.05%, which was significantly higher than that for the group without MMP-2, demonstrating the enzyme-responsiveness of the nano-drug delivery system. In addition, the cellular uptake and tumor accumulation of PEG-GPLGVRG-PBLA were better than those of PEG-PBLA, and the blank PEG-GPLGVRG-PBLA showed high biocompatibility . These findings indicate that the enzyme-responsive nano SN-38 delivery system could provide new opportunities in tumor therapy.
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