ABSTRACT
Oral inflammatory diseases are highly prevalent in the worldwide population. Topical treatment of inflammation is challenging due to dilution effects of saliva and crevicular fluid. Thus, there is a great medical need to develop smart anti-inflammatory drug delivery systems for mucosa treatment. We compared two promising anti-inflammatory dendritic poly(glycerol-caprolactone) sulfate (dPGS-PCL) polymers for their applicability to the oral mucosa. Using an ex vivo porcine tissue model, cell monolayers, and full-thickness 3D oral mucosal organoids, the polymers were evaluated for muco-adhesion, penetration, and anti-inflammatory properties. The biodegradable dPGS-PCL97 polymers adhered to and penetrated the masticatory mucosa within seconds. No effects on metabolic activity and cell proliferation were found. dPGS-PCL97 revealed a significant downregulation of pro-inflammatory cytokines with a clear preference for IL-8 in cell monolayers and mucosal organoids. Thus, dPGS-PCL97 exhibits excellent properties for topical anti-inflammatory therapy, suggesting new therapeutic avenues in the treatment of oral inflammatory diseases.
Subject(s)
Interleukin-8 , Mouth Mucosa , Animals , Swine , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Polymers/pharmacology , Drug Delivery SystemsABSTRACT
Targeted delivery and extended blood circulation of anticancer drugs have been the challenges for decreasing the adverse side effects and improving the therapeutic efficiency in cancer chemotherapy. Herein, we present a drug delivery system (DDS) based on biodegradable dendritic polyglycerol sulfate-bearing poly(caprolactone) (dPGS-PCL) chains, which has been synthesized on 20 g scale using a straightforward two-step protocol. In vivo fluorescence imaging demonstrated a significant accumulation of the DDS in the tumor environment. Sunitinib, an anticancer drug, was loaded into the DDS and the drug-induced toxicity was investigated in vitro and in vivo. The drug encapsulated in dPGS-PCL and the free drug showed similar toxicities in A431 and HT-29 cells, and the cellular uptake was comparable. The straightforward and large-scale synthesis, the organic solvent-free drug-loading approach, together with the tumor targetability of the biodegradable dendritic polyglycerols, render this copolymer a promising candidate for targeted cancer nanomedicine drug delivery systems.
Subject(s)
Antineoplastic Agents , Cytostatic Agents , Neoplasms , Glycerol , Humans , Neoplasms/drug therapy , Polymers , SulfatesABSTRACT
Dendritic polyglycerol-co-polycaprolactone (PG-co-PCL)-derived block copolymers are synthesized and explored as nanoscale drug delivery platforms for a chemotherapeutic agent, gemcitabine (GEM), which is the cornerstone of therapy for pancreatic ductal adenocarcinoma (PDAC). Current treatment strategies with GEM result in suboptimal therapeutic outcome owing to microenvironmental resistance and rapid metabolic degradation of GEM. To address these challenges, physicochemical and cell-biological properties of both covalently conjugated and non-covalently stabilized variants of GEM-containing PG-co-PCL architectures have been evaluated. Self-assembly behavior, drug loading and release capacity, cytotoxicity, and cellular uptake properties of these constructs in monolayer and in spheroid cultures of PDAC cells are investigated. To realize the covalently conjugated carrier systems, GEM, in conjunction with a tertiary amine, is attached to the polycarbonate block grafted from the PG-co-PCL core. It is observed that pH-dependent ionization properties of these amine side-chains direct the formation of self-assembly of block copolymers in the form of nanoparticles. For non-covalent encapsulation, a facile "solvent-shifting" technique is adopted. Fabrication techniques are found to control colloidal and cellular properties of GEM-loaded nanoconstructs. The feasibility and potential of these newly developed architectures for designing carrier systems for GEM to achieve augmented prognosis for pancreatic cancer are reported.
Subject(s)
Deoxycytidine/analogs & derivatives , Drug Delivery Systems , Glycerol/chemistry , Nanoparticles/chemistry , Pancreatic Neoplasms/drug therapy , Polymers/chemistry , Cell Death/drug effects , Cell Line, Tumor , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Drug Carriers/chemistry , Endocytosis/drug effects , Glycerol/chemical synthesis , Humans , Hydrogen-Ion Concentration , Nanoparticles/ultrastructure , Pancreatic Neoplasms/pathology , Polycarboxylate Cement/chemical synthesis , Polycarboxylate Cement/chemistry , Polymers/chemical synthesis , Proton Magnetic Resonance Spectroscopy , Spheroids, Cellular/drug effects , Spheroids, Cellular/pathology , Tissue Scaffolds/chemistry , Gemcitabine , Pancreatic NeoplasmsABSTRACT
Inflammatory processes are beneficial responses to overcome injury or illness. Knowledge of the underlying mechanisms allows for a specific treatment. Thus, synthetic systems can be generated for a targeted interaction. In this context, dendritic polyglycerol sulfates (dPGS) have been investigated as anti-inflammatory compounds. Biodegradable systems are required to prevent compound accumulation in the body. Here we present biodegradable analogs of dPGS based on hyperbranched poly(glycidol- co-caprolactone) bearing a hydrophilic sulfate outer shell (hPG- co-PCLS). The copolymers were investigated regarding their physical and chemical properties. The cytocompatibility was confirmed using A549, Caco-2, and HaCaT cells. Internalization of hPG- co-PCLS by A549 and Caco-2 cells was observed as well. Moreover, we demonstrated that hPG- co-PCLS acted as a competitive inhibitor of the leukocytic cell adhesion receptor L-selectin. Further, a reduction of complement activity was observed. These new biodegradable dPGS analogs are therefore attractive for therapeutic applications regarding inflammatory diseases.
