# F127/Cisplatin Microemulsions: _In Vitro_, _In Vivo_ and Computational Studies
## 1 Introduction  
Cisidamminedichloroplatinum (II), commonly known as Cisplatin (Cis), is a platinum coordinate compound that is highly soluble in water and soluble in N,N-dimethylformamide,and dimethylprimanide [1]. It acquired FDA approval in 1978 for the treatment of testicular and ovarian cancer. It also holds the potential for the treatment of lung, ovarian, and breast cancers [2,3], and it has recently being explored for the treatment of bladder cancer [3,4]. Cis has been extensively used in clinical studies, but the mechanism of internalization in cancer cells remains ambiguous. The existing studies, however, demonstrate that Cis is taken up by the cells via passive diffusion, or the CTR1 cell membrane protein aids in the Cis influx [5]. Cis has a partition coefficient (\(\log\text{P}_{\text{octanol/water}}\)) value of \(-2.19\), making it a hydrophilic molecule; therefore, it has reduced permeation across the biological membranes and reduced retention [6]. Thus, despite its clinical advantages, Cis suffers from low bioavailability, rapid blood clearance, and severe nephrotoxicity. Moreover, multi-drug resistance (MDR) is developed by the cancer cells due to prolonged treatment and is one of the major causes of the failure of chemotherapy [7]. The traditional chemotherapeutic drug delivery approaches suffer from the off-site drug accumulation at the desired site. This often leads to organ toxicity [8]. As a result of recent advances in nanomedicine, the drug accumulation/confinement may be improved at the target site with the possibility of the controlled release of the drug in the tumor matrix or cells, thus reducing the dose-dependent nephrotoxicity. Moreover, the nanocarriers are accumulated in the cancer cells via the enhanced permeability and retention effect (EPR), thereby increasing the chemotherapeutic activity [9]. Thereupon, nanotechnology-based approaches effectively entrap the drug and improve the pharmacokinetic profile of the drug as well as its biodistribution profile. Microemulsion technology is extensively used because of the thermodynamic stability and the reduced particle size of the colloid system, which allows the encapsulation of hydrophilic and hydrophobic moieties. Moreover, microemulsions improve the stability and bioavailability of drugs and can also solubilize drugs of a different nature [10]. Some special types of microemulsions, being responsive to certain stimuli, such as pH, temperature, light, or magnetic fields [11], can also be conceived as intelligent nano-robots, opening fascinating horizons in many industries and research fields, including drug release. In fact, controlling the microemulsion breaking can be a valuable strategy to finely modulate the drug delivery process in terms of both time (release kinetics) and space (release location). Microemulsions are usually composed of water, oil, a surfactant, drug, and a cosurfactant and are characterized as oil in water (O/W), water in oil (W/O), and bicontinuous systems [12]. O/W microemulsions are advantageous as the continuous phase is water and, hence, they are easy to scale-up towards an industrial level [13]. Several factors must be considered, such as selected oil, surfactant, and co-surfactant to optimize the drug encapsulation. In microemulsions, surfactants minimize the hydrophobic interactions between the phases to maintain stability [14]. The microemulsions composed of non-ionic surfactants hold technological versatility as such nanosystems offer stability and protection to the entrapped drug from the tumor or cancer microenvironment, along with physiological conditions of the body [15]. Moreover, their use in pharmaceutical formulations has been approved by the regulatory authorities [16]. Pluronics are triblock copolymers with the general structure (polyethylene glycol)-block-(polypropylene glycol)-block-(polyethylene glycol).