Synthesis and characterisation of the PNIPAM-grafted MPS-MCM-41 for thermoresponsive triggered drug delivery for cancer pain control

Abstract

Cancer pain is one of the most common and challenging symptoms faced in the palliative care. It can be breakthrough pain, which requires a fast-acting opioid formulation, or chronic pain, which is clinically controlled with 24 h opioid medications. Due to the significant risk of opioid misuse and diversion, infection, overdose, bodily invasiveness, movement restriction, and the high cost of hospitalisation, current and emerging delivery systems are unable to provide opioids efficiently to control cancer pain. This study proposed a novel opioid delivery system for the treatment of cancer pain based on mesoporous silica nanoparticles (MSNs), gold nanoparticles (AuNPs), and the thermo-responsive poly (N-isopropyl arylamide) (PNIPAM). Because of the complexity of the proposed system, this work concentrated on the core of the triggered system, which is the quantification and characterisation of drug entrapment and in vitro drug release in response to thermal triggers. The goal was to create a PNIPAM-grafted MPS-MCM-41 for thermosensitive TDDS for pain control. Toward achieving this goal, ideal characteristics of delivery systems for treating cancer pain were first recommended after a comprehensive evaluation of the present delivery systems used for cancer pain control. After that, a thorough investigation was carried out to address the challenges with drug entrapment into MSNs, including the measurement technique and verifying that the drug was loaded inside the silica nanoparticles' mesopores. As an alternative to the time-consuming, expensive, and highly variable standard method of high-performance liquid chromatography (HPLC), a quick, sensitive, and inexpensive analytical methodology based on thermogravimetric analysis (TGA) was developed. A novel way of characterising the drug entrapment method of adsorption and incipient wetness impregnation for drug entrapment into the pores of MSNs was developed utilising iii differential scanning calorimetry (DSC) and an in vitro dissolution study. Subsequently, the hybrid PNIPAM-grafted MPS-MCM-41 was synthesised, and its properties, including the thermo-responsive triggered release behaviour, were studied. The results demonstrated that the proposed TGA approach was a quick (60 min), sensitive (limit of detection = 0.77 %, w/w), and economical substitute for the HPLC. The results of the multiple comparison analysis indicate that there was no significant (p > 0.05) difference in the drug entrapment measurements obtained using the two methods of TGA and HPLC. The results from the DSC and the in vitro dissolution study showed a high crystallinity degree for the MSNs loaded with the adsorption method with a slower release profile, compared to a low degree of crystallinity with a faster release profile with the incipient wetness method, implying the presence of an amorphous drug inside the silica pores. The thermo-responsive release behaviour of the hybrid PNIPAM-grafted MPS-MCM-41 was confirmed, which showed a faster rate of release at temperatures above the polymer transition temperature, at 40 °C and 50 °C, compared to that below the transition temperature, at 25 °C. The cumulative percentages of drug released were 37.1 ± 5.1 %, and 38.6 ± 4.2 %, at 40 ºC, and 50 ºC, respectively, compared to 21.3 ± 5.5 % at 25 ºC. This discovery suggests that the hybrid PNIPAM-grafted MPS-MCM-41 may be able to construct a thermo-responsive TDDS that can serve as a core platform for a photothermal TDDS for cancer pain control.