Characterization and Equilibrium Study of Drug Release of pH-Responsive Chitosan-graft-Maleic Film

    This paper reports on a pH responsive material and a mathematical model for a drug release study. This material can be applied as a tumor drug carrier, because the tumor tissue has a different pH (5.7–7.8) compared to the healthy tissue (7.3–7.4). Maleic anhydride (MA) is introduced into the chitosan (CTS) backbone to create a polyampholyte chitosan-graft-maleic (CgM) film that has a pH responsive property. The success of the reaction is confirmed by Fourier transform infrared spectroscopy, which shows a new peak at 1705cm^-1. The acidic content and mechanical strength of the material increase with the MA:CTS ratio. Our result shows that the pH responsive property of this material appears at a ratio of 4:2 (weight MA/weight CTS). The equilibrium swelling ratio provides information regarding the isoelectric point, which is obtained at pH 6. The drug release study involves adsorption isotherms and moving boundaries cases. Our calculation results show that the D_e value varies from 2.71 × 10^-7 to 6.37 × 10^-7 cm²/min. The Henry constants vary by approximately 10² to 10³ in the order of magnitude. The Langmuir maximum adsorption capacity is approximately 10⁰ to 10² mmol/g in the order of magnitude.

Adsorption isotherm; Chitosan-graft-maleic; Mathematical model; Moving boundary; pH-responsive

Recently, the development of biomaterials has shifted from active materials to “smart” materials. These smart materials can respond or adjust depending on their environment (Zhang et al., 2019). In the field of drug delivery systems, several stimuli are used, such as radiation intensity, temperature, enzyme, magnetic field, and pH (Qian et al., 2019). Among these, pH is the most interesting because the human body naturally has a wide range of pH values of approximately 2–7.4 (Manga & Jha, 2017). This stimulus has specific values in different biological conditions; for example, in tumor tissue, the pH value is approximately 5.7–7.8, which is different from that in normal tissue (approximately 7.3–7.4) (Qian et al., 2019). Hence, drug release is expected to be specific to the tumor tissue rather than the healthy tissue.

     The pH-responsive drug delivery system commonly uses hydrogel technology. However, to obtain a pH-responsive hydrogel, the hydrogel should be formed of a   polyampholyte, which exhibits different swelling behaviors depending on the pH value and salt concentration of the environment (Su & Okay, 2017). This property is attributed to the presence of anionic and cationic functional groups along the polymer chains. As polyampholyte has both types of charges, the density of each charge type is important. The charge density is affected by the salt concentration or the pH of the environment. When the environment is acidic, the cationic functional groups have a higher density, while in basic media, the density of the anionic functional groups is higher. There is a pH point at which both functional groups have the same density, which is called the isoelectric point (IEP) (Kono et al., 2013). Thus, a polyampholyte can be synthesized from cationic or anionic polymers.
     Chitosan (CTS), (1-4)-2-amino-2-deoxy-?-D-glucan, is known as a natural polycationic saccharide (Kusumastuti et al., 2017a) and the second most abundant polysaccharide after cellulose (Muharam et al., 2015). It can be safely used as a raw biomaterial (Wibowo et al., 2021), owing to its properties such as biocompatibility, biodegradation, nontoxicity, and the ability to mimic the native properties of a tissue (Morgado et al., 2015). CTS also exhibits a suitable film-forming ability (Timotius et al., 2020). Therefore, it is reasonable to use CTS as a raw material to build 2D hydrogels. Because CTS is polycationic, it needs to be modified to obtain polyampholyte properties. Hasipoglu et al. (2005) modified CTS with maleic acid through grafting copolymerization by using ceric ammonium nitrate as the initiator. This resulted in chitosan-graft-maleic (CgM), which acts as a polyampholyte. Zhou et al. (2017) grafted maleic anhydride (MA) into CTS without any initiator and further used it as a potential wound dressing. In our previous work (Timotius et al, 2019), we observed that this material can be used as a drug delivery system. We also observed a compatible mathematical model of drug release kinetics in this system (Timotius et al., 2020).
    Considering that this material has been extensively studied, in this study, a CgM film was synthesized and characterized as a potential pH-responsive material. The drug release study was conducted at various pH values. A mathematical model was derived, involving several adsorption isotherm models, such as the thermodynamic equilibrium model, namely the Henry model, Langmuir model, and Freundlich model. The moving boundary caused by the film degradation was also involved in the model. Curcumin was used as the drug model in the drug release study and was identified as a cancer medicine. 

The grafting of MA and CTS is successfully performed in this study. Increasing the MA:CTS ratio leads to an increase in the tensile strength and a reduction in the elongation at break. The MA:CTS ratio that results in polyampholyte properties is obtained at 2:1 (w/w) and is denoted as CgM-42. The IEP of CgM-42 is identified at pH 6, which is obtained from the equilibrium swelling ratio study. The degradation behavior is consistent with the swelling result. In the drug release study, all adsorption isotherm models fit the data. The value of D_e is not affected by the pH. However, the adsorption equilibrium parameters are strongly influenced by the pH. The value varies from 2.71 × 10^-7 to 6.37 × 10^-7 cm²/min. The Henry constants vary by approximately 102 to 10³ in the order of magnitude, and the Langmuir maximum adsorption capacity is approximately 10⁰ to 10² mmol/g. The trend of C_m is consistent with the equilibrium swelling ratio. These results show that this film can be used for pH-responsive drug delivery systems.

       This study was funded by the Ministry of Education and Culture of Indonesia in the scheme of PDUPT with contract number no 2846/UN1.DITLIT/DIT-LIT/PT/2020.

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