RESUMO
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.
Assuntos
Antineoplásicos , Citostáticos , Neoplasias , Glicerol , Humanos , Neoplasias/tratamento farmacológico , Polímeros , SulfatosRESUMO
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.
Assuntos
Desoxicitidina/análogos & derivados , Sistemas de Liberação de Medicamentos , Glicerol/química , Nanopartículas/química , Neoplasias Pancreáticas/tratamento farmacológico , Polímeros/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Portadores de Fármacos/química , Endocitose/efeitos dos fármacos , Glicerol/síntese química , Humanos , Concentração de Íons de Hidrogênio , Nanopartículas/ultraestrutura , Neoplasias Pancreáticas/patologia , Cimento de Policarboxilato/síntese química , Cimento de Policarboxilato/química , Polímeros/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Alicerces Teciduais/química , Gencitabina , Neoplasias PancreáticasRESUMO
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.