RESUMO
Water-soluble polymers of cyclodextrins (CyD) can be easily obtained in alkaline media following polycondensation of the naturally occurring monomers in the presence of a crosslinking agent. They can be further modified to customize specifically functionalized architectures. Compared to other macromolecules natural and not, the CyD polymers are endowed with a unique feature, the cone-shaped cavities where they can host guests of various nature. This element has sollicited interest in this class of molecules for a wide range of applications including the biomedical field, in particular drug delivery. The CyD polymers display excellent behavior in terms of water solubility and solubilizing power towards drugs and therapeutic agents that are incompatible with biological fluids. Moreover, they can load more than one type of therapeutic agent in a single system thus allowing to implement combination therapy. In spite of some very promising results as delivery systems, their potentialities remain limited by some intrinsic hurdles. Herein, we comment on their limits mainly related to the production process and the possible solutions to overcome them, giving an outlook on their assets for innovation in disease treatment.
Assuntos
Ciclodextrinas , Polímeros , Solubilidade , Água , Ciclodextrinas/química , Água/química , Polímeros/química , Humanos , Sistemas de Liberação de Medicamentos , Portadores de Fármacos/química , CeluloseRESUMO
We explored a series of cyclodextrin (CyD) polymers composed either of a single CyD type or a mixture of two CyD types to encapsulate simultaneously different compounds with potential therapeutic interest for multimodal prostate cancer treatment. New mixed CyD polymers were prepared in alkaline water starting from the naturally occurring monomers and a low-cost crosslinking agent. Batches of 200 g of polymer were easily obtained. By means of optical spectroscopy we proved the co-encapsulation of 3 compounds in the polymers: the drugs cabazitaxel (CBX) and bicalutamide (BIC), and the photosensitizer chlorin e6 (Ce6). pßCyD and mixed pαßCyD polymers performed best for single drug solubilization. In the co-encapsulation of BIC and CBX by pßCyD and pαßCyD, pßCyD stands out in drug solubilization ability. Avoiding the use of organic solvents, it was possible to dissolve up to 0.1 mM CBX with 10 mg ml-1 pßCyD polymer and, with 100 mg ml-1, even 1.7 mM BIC, a 100-fold improvement compared to water. Spectroscopic studies afforded the binding constants of CBX and BIC with pßCyD forming complexes of 1 : 2 stoichiometry (drug : CyD) and CBX displayed significantly higher affinity. Also DFT calculations suggested that the drugs are more stable when complexed by two CyD units. Ce6 could be encapsulated simultaneously with the other two drugs in pßCyD and, most importantly, is able to produce singlet oxygen efficiently. Thanks to a single inexpensive CyD-based polymer we were able to produce a three-in-one platform for future implementation of combined chemotherapy and photodynamic therapy. These achievements are most relevant as nanomedicines are continuously proposed but their potential for translation to the pharma industry is compromised by their limited potential for industrial upscale.
RESUMO
In the quest for new therapies targeting hypoxia, aromatic endoperoxides have intriguing potential as oxygen releasing agents (ORAs) able to free O2 in tissues upon suitable trigger. Four aromatic substrates were synthesized and the formation of their corresponding endoperoxides was optimized in organic solvent upon selective irradiation of Methylene Blue, a low-cost photocatalyst, producing the reactive singlet oxygen species. Complexation of the hydrophobic substrates within a hydrophilic cyclodextrin (CyD) polymer allowed their photooxygenation in homogeneous aqueous environment using the same optimized protocol upon dissolution in water of the three readily accessible reagents. Notably, reaction rates were comparable in buffered D2 O and organic solvent and, for the first time, the photooxygenation of highly hydrophobic substrates was achieved for millimolar solutions in non-deuterated water. Quantitative conversion of the substrates, straightforward isolation of the endoperoxides and recovery of the polymeric matrix were achieved. Cycloreversion of one ORA to the original aromatic substrate was observed upon thermolysis. These results hold great potential for the launch of CyD polymers both as reaction vessels for green, homogeneous photocatalysis and as carrier for the delivery of ORAs in tissues.