Fabrication, rheological analysis, and in vitro characterization of in situ chemically cross‐linkable thermogels as controlled and prolonged drug depot for localized and systemic delivery

Abstract

5‐Fluorouracil (5‐FU) is widely used against many types of solid cancer in clinics. However, because of its limitations such as short half‐life, poor oral absorption and rapid clearance by dihydropyrimidine dehydrogenase have limited its applications. In current study, new in situ chemically grafted thermogels for prolonged drug release are formed on the basis of poloxamer 407 (PF127) and carboxymethyl chitosan (CMCS) using glutaraldehyde as cross‐linking agent. The phase transition from sol to gel state at body temperature was confirmed by tube titling, rheological analysis, and optical transmittance determinations. Swelling and drug release experiments conducted at various pH and temperature demonstrated that developed formulations are thermoresponsive with maximum swelling and release below critical gelation temperature (CGT) (pH 7.4, 25°C). Cells growth inhibition study confirmed the biocompatibility of thermogels against L929 cell lines. Methyl thiazolyl tetrazolium (MTT) assay confirmed that 5‐FU–loaded thermogels have the potential to cause cells death against HeLa and MCF‐7 cancer lines. The IC50 values calculated for pure 5‐FU solution (27 ± 0.81 μg/mL for HeLa and 24 ± 0.58 μg/mL for MCF‐7) were found higher in comparison with 5‐FU–loaded thermogels, against HeLa (17 ± 0.39 μg/mL) and MCF‐7 (14 ± 0.67 μg/mL). Fourier transform infrared (FTIR) confirmed the new structure formation and chemical grafting between PF127 and CMCS. Thermogravimetric (TG) and differential scanning calorimetry (DSC) analyses proved the phase transition around physiologic temperature range, while scanning electron microscopy (SEM) analysis displayed the presence of connected pores in the cross section of thermogels facilitating the uptake of solvents and drug particles. Altogether, results concluded that developed chemically grafted thermogels can be used in vivo for prolonged drug release after subcutaneous administration.

RETRACTED: Poly (N-vinylcaprolactam-grafted-sodium alginate) Based Injectable pH/Thermo Responsive In Situ Forming Depot Hydrogels for Prolonged Controlled Anticancer Drug Delivery; In Vitro, In Vivo Characterization and Toxicity Evaluation

“…For stability determination of the gels at LCST (33 °C), samples were scrutinized by frequency sweep test. The stability of samples was monitored by noting change in G′ and G″ at 0.01–50 Hz frequency range at 1% strain [ 37 ].…”

“…The transmittances were measured at digital water bath under 25–45 °C range using 10 mm × 10 mm × 40 mm disposable cuvettes. Prior to transmittance analysis, every test sample was kept at that temperature for 5 min [ 37 ].…”

“…At regular time interim, 2 mL aliquot was withdrawn and analyzed for release using UV-Visible spectrophotometer at 265 nm. The sink conditions were maintained by adding fresh media [ 37 , 40 ]. The cumulative % release was calculated by using following formula; where: 50 designates volume of medium in ml; Cn and Cn−1 refers to the concentration after n and n − 1 times, respectively; 2 refers to the withdrawn volume for analysis in ml; and m 0 designates the drug amount (mg) loaded in gels.…”

Hybrid Thermo-Responsive Polymer Systems and Their Biomedical Applications

“…In mechanism B, the number of micelles remains unchanged during stage iii, but their size is increased with temperature so that the intermicellar distance is shortened and gelation through entanglements is allowed. Reproduced with permission from Lau et al 2004 carboxyl groups present when increasing the contents of CMCS within the formulation also resulted in an increase in drug release, particularly at pH7.4, due to a resulting increase in water uptake and subsequently drug diffusion (Khan et al, 2018).…”

<p>Burgeoning Polymer Nano Blends for Improved Controlled Drug Release: A Review</p>

“…8 In order to acquire novel and beneficial controlled drug release, different approaches among polymers have emerged-such as injectable hydrogels, 9 direct implantation, 10 crosslinked micelles, 11 injectable suspension 12 and depots. 13 As time goes by, biopolymers of various nanometer sizes, shapes, and surface properties have played a crucial role as CDDSs 14 and their synergic effects have ameliorated drug entrapment and mechanical property concerns. 15 It is an indisputable fact that polymers-either natural or synthetic-have become predominantly important materials as CDDSs, providing the weight, consistency and volume for the beneficial administration of drugs.…”