Publicação
Encapsulation of Curcumin Derivative in Chitosan Nanoparticles for Diabetes: an In Vitro Study
| Resumo: | Type 2 Diabetes Mellitus (T2DM) is a multifactorial and complex metabolic disorder associated with hyperglycemia caused by impaired insulin secretion and insulin resistance (IR), accompanied by inflammation, oxidative stress, and micro- or macrovascular dysfunctions, ultimately emerging into chronic complications. Curcumin, a polyphenolic compound extracted from Curcuma longa, is widely recognized for its strong anti-inflammatory, antioxidant, and antidiabetic activities. Numerous studies have demonstrated its therapeutic potential in T2DM, highlighting its ability to enhance insulin sensitivity, regulate blood glucose and lipid levels, and mitigate inflammation and oxidative stress. However, its clinical application is limited by its low aqueous solubility, poor bioavailability, and rapid metabolism. Various chemical strategies have been developed to address these challenges, including drug delivery systems, adjuvant therapies, and chemical modifications to improve curcumin’s stability, solubility, and biological efficacy. In the present study, two approaches were adopted: (1) chemical modification of the curcumin molecule to obtain a curcumin derivative, designated as derivative 27, and (2) encapsulation of curcumin and curcumin derivative into chitosan nanoparticles (NPs). Derivative 27 was designed to enhance curcumin’s pharmacological effects at low doses by incorporating specific chemical modifications, whose modified methodology of synthesis and proven therapeutic efficacy in an animal model of T2DM have been previously described by the group. Chitosan is a naturally derived polymer obtained by the deacetylation of chitin, which enables the development of stable and versatile nanocarriers that enhance drug bioavailability, stability, targeted delivery, and may decrease drug toxicity. Chitosan NPs have gained significant attention due to their remarkable properties such as biocompatibility, biodegradability, low toxicity, and ability to encapsulate a wide range of therapeutic agents. This work describes the optimization of a method to produce chitosan NPs to encapsulate curcumin and its derivative using the ionotropic gelation method. The NPs showed an average size of approximately 500 nm, PDI values ranging from 0.3 to 0.4, and zeta potential ranging from + 45 mV to + 48 mV. TEM images revealed spherical morphology, the presence of very small NPs (< 100 nm), and some NPs aggregation, which explains the relatively high PDI. The FTIR analysis suggested the successful encapsulation of curcumin and derivative 27 into chitosan NPs. The encapsulation efficiency (EE) of both compounds was notably high (> 80 %), with derivative 27 demonstrating superior EE. The NPs also demonstrated good stability at 4 ºC and 25 ºC for at least 35 days. Afterwards, the cytotoxicity and the anti-inflammatory and antioxidant effects of the NPs were evaluated in vitro. Curcumin-loaded chitosan (ChiCur) NPs and derivative 27-loaded chitosan (ChiD27) NPs were tested in RAW 264.7 and KeratinoSensTM cell lines, along with the empty nanocarrier and free compounds for comparative analysis. All NPs exhibited a non-cytotoxic profile, confirming their safety for potential therapeutic applications. The encapsulation of derivative 27 significantly reduced its cytotoxicity compared to its free form, thereby ensuring better biocompatibility, particularly at higher concentrations. Derivative 27 strongly inhibited NO and ROS production in RAW 264.7 cells, demonstrating potent anti-inflammatory and antioxidant activities, with greater efficacy than curcumin at equimolar concentrations. However, its encapsulation led to a more moderate inhibitory effect, likely due to a controlled and sustained release of the compound. Nonetheless, ChiD27 NPs outperformed ChiCur NPs, further reinforcing their enhanced therapeutic potential. Additionally, the nanocarrier alone exhibited anti-inflammatory properties by significantly reducing NO levels, highlighting the dual contribution of the nanocarrier and the active compounds in modulating inflammation. Furthermore, derivative 27 significantly induced luciferase activity in KeratinoSensTM cells, confirming Nrf2 pathway activation. This was not observed after curcumin treatment in the range of equimolar concentrations tested. Again, the encapsulation of derivative 27 led to a more moderate effect, indicating that derivative 27 was not completely released from the chitosan NPs. In conclusion, it was demonstrated that the encapsulation of derivative 27 into chitosan NPs can optimize its therapeutic efficacy by reducing cytotoxicity and ensuring a controlled and sustained release. |
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| Autores principais: | Oliveira, Dafne Simões de |
| Assunto: | Type 2 Diabetes Mellitus Inflammation Oxidative stress Curcumin derivative Chitosan nanoparticles Diabetes Mellitus Tipo 2 Inflamação Stress oxidativo Derivado da curcumina Nanopartículas de quitosano |
| Ano: | 2025 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso embargado |
| Instituição associada: | Universidade de Coimbra |
| Idioma: | inglês |
| Origem: | Estudo Geral - Universidade de Coimbra |
| Resumo: | Type 2 Diabetes Mellitus (T2DM) is a multifactorial and complex metabolic disorder associated with hyperglycemia caused by impaired insulin secretion and insulin resistance (IR), accompanied by inflammation, oxidative stress, and micro- or macrovascular dysfunctions, ultimately emerging into chronic complications. Curcumin, a polyphenolic compound extracted from Curcuma longa, is widely recognized for its strong anti-inflammatory, antioxidant, and antidiabetic activities. Numerous studies have demonstrated its therapeutic potential in T2DM, highlighting its ability to enhance insulin sensitivity, regulate blood glucose and lipid levels, and mitigate inflammation and oxidative stress. However, its clinical application is limited by its low aqueous solubility, poor bioavailability, and rapid metabolism. Various chemical strategies have been developed to address these challenges, including drug delivery systems, adjuvant therapies, and chemical modifications to improve curcumin’s stability, solubility, and biological efficacy. In the present study, two approaches were adopted: (1) chemical modification of the curcumin molecule to obtain a curcumin derivative, designated as derivative 27, and (2) encapsulation of curcumin and curcumin derivative into chitosan nanoparticles (NPs). Derivative 27 was designed to enhance curcumin’s pharmacological effects at low doses by incorporating specific chemical modifications, whose modified methodology of synthesis and proven therapeutic efficacy in an animal model of T2DM have been previously described by the group. Chitosan is a naturally derived polymer obtained by the deacetylation of chitin, which enables the development of stable and versatile nanocarriers that enhance drug bioavailability, stability, targeted delivery, and may decrease drug toxicity. Chitosan NPs have gained significant attention due to their remarkable properties such as biocompatibility, biodegradability, low toxicity, and ability to encapsulate a wide range of therapeutic agents. This work describes the optimization of a method to produce chitosan NPs to encapsulate curcumin and its derivative using the ionotropic gelation method. The NPs showed an average size of approximately 500 nm, PDI values ranging from 0.3 to 0.4, and zeta potential ranging from + 45 mV to + 48 mV. TEM images revealed spherical morphology, the presence of very small NPs (< 100 nm), and some NPs aggregation, which explains the relatively high PDI. The FTIR analysis suggested the successful encapsulation of curcumin and derivative 27 into chitosan NPs. The encapsulation efficiency (EE) of both compounds was notably high (> 80 %), with derivative 27 demonstrating superior EE. The NPs also demonstrated good stability at 4 ºC and 25 ºC for at least 35 days. Afterwards, the cytotoxicity and the anti-inflammatory and antioxidant effects of the NPs were evaluated in vitro. Curcumin-loaded chitosan (ChiCur) NPs and derivative 27-loaded chitosan (ChiD27) NPs were tested in RAW 264.7 and KeratinoSensTM cell lines, along with the empty nanocarrier and free compounds for comparative analysis. All NPs exhibited a non-cytotoxic profile, confirming their safety for potential therapeutic applications. The encapsulation of derivative 27 significantly reduced its cytotoxicity compared to its free form, thereby ensuring better biocompatibility, particularly at higher concentrations. Derivative 27 strongly inhibited NO and ROS production in RAW 264.7 cells, demonstrating potent anti-inflammatory and antioxidant activities, with greater efficacy than curcumin at equimolar concentrations. However, its encapsulation led to a more moderate inhibitory effect, likely due to a controlled and sustained release of the compound. Nonetheless, ChiD27 NPs outperformed ChiCur NPs, further reinforcing their enhanced therapeutic potential. Additionally, the nanocarrier alone exhibited anti-inflammatory properties by significantly reducing NO levels, highlighting the dual contribution of the nanocarrier and the active compounds in modulating inflammation. Furthermore, derivative 27 significantly induced luciferase activity in KeratinoSensTM cells, confirming Nrf2 pathway activation. This was not observed after curcumin treatment in the range of equimolar concentrations tested. Again, the encapsulation of derivative 27 led to a more moderate effect, indicating that derivative 27 was not completely released from the chitosan NPs. In conclusion, it was demonstrated that the encapsulation of derivative 27 into chitosan NPs can optimize its therapeutic efficacy by reducing cytotoxicity and ensuring a controlled and sustained release. |
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