The system of timely control release of drugs at the desired site of the body is considered a therapeutically potential approach. This technique offers a steady-state concentration of principal drug throughout the treatment period. Controlled drug delivery is a constantly growing field in the pharmaceutical industry and provides numerous biomedical applications. The method of control drug delivery is gaining dominance due to its ability to improve the therapeutic effects of conventionally available drugs [1], [2], [3]. Nano scale drug delivery systems smartly deliver low solubility and permeability drugs to the target site of action. This technique has been extensively reported due to drug stability and efficient drug delivery. Several nanocarriers for efficient drug delivery, such as micelles, vesicles and metal nanoparticles have been previously reported. Conversely, the polymeric nanoparticles possess great capability and are widely used in the treatment of cancer [4], [5], [6]. Although recently, naturally occurring polysaccharides have gained widespread use in the field of drug delivery as a drug vehicles (nanocarriers) due to their excellent biocompatibility, non-toxicity, low cost, biodegradability, renewability, high drug loading capability, and ability to sustain drug release in various physicochemical environments [7], [8]. Among various nanocarriers, supramolecular amphiphile cavitands have been extensively evaluated [9], [10], [11]. Supramolecular amphiphiles structures have the capability to organize into cavitand shapes, that generally involve noncovalent interactions such as electrostatic interactions, hydrogen bonding, Pi-Pi interaction, “Van der Waals” forces, hydrophobic interactions, and host-guest interactions [12], [13], [14]. Self assembling of supramolecular amphiphile into a well defined structure depends on the nature and solubility of the drug. The amphiphilic supramolecular macrocycles exhibit surfactants like those of non-ionic surfactants. The non-ionic surfactants are those amphiphilic molecules which possess polar head and non-polar tail and have excellent property to self-assemble in aqueous media and form membrane bilayer [15]. Since of their amphiphilic nature, macrocycles have unique hydrophobic and hydrophilic regions, which enable them to form micelles and act as effective surfactants. Therefore, these can enhance the solubility and stability of hydrophobic drugs in aqueous environments, which is crucial for oral drug delivery systems. The surfactant nature and nanostructure formation of amphiphilic macrocycles enhances drug permeability of drugs across the intestinal barrier, facilitating their absorption. The niosomal formulation further enhances oral bioavailability and improves efficacy of the drug by ensuring that it is released at the desired site of action. The drug release at the target site potentially reduces side effects associated with systemic distribution of the drug [16].

Supramolecular amphiphile after, encapsulating the drug in the vesicles through host-guest interaction provide significant stability to the drug in the gastric pH environment [17], [18], [19]. Supramolecular amphiphile structures deliver a greater amount of drugs due to their large surface area and cage like cavity in the macromolecular structure. These distinct characteristics of supramolecular amphiphile tuned according to amphiphilicity and can radially assemble and disassemble [20]. Active pharmaceutical ingredients with poor solubility and permeability compromise their therapeutic bioavailability level and efficacy. Calix [4] Resorcinarene (CR) based macrocycle amphiphiles are considered suitable cavitand for administration of low soluble and permeable dugs. Calix [4] Resorcinarene based macrocycle amphiphiles are commonly synthesized by condensing aliphatic or aromatic aldehydes. The formation of host-guest drug encapsulation complexes with Calix [4] Resorcinarene depends on structure of CR. Previous studies have reported Calix [4] Resorcinarene based macrocycle amphiphiles as highly safe, biocompatible, biodegradable, self-assembled and water soluble vehicle in nano drug delivery systems. Nanomedicines are an amalgamation of medicine and nanotechnology [21], [22], [23], [24]. The purpose of such macrocylic amphiphiles is to reduce the exposure of healthy tissue/organs to drugs and facilitate precise drug delivery and body elimination [25], [26]. Consequently, the recently synthesized nanocarriers have great and efficient abilities to enhance the oral bioavailability of poorly water soluble drugs and reducing their side effects.

Amphotercin-B (Amph-B) is a drug of choice for the treatment of Leishmaniasis protozoa, fungal infections associated with neuropathic pain linked and HIV infection [27], [28], [29]. According to the biopharmaceutics classification system, AmphB is classified as BCS-IV drug. In BCS-IV class drugs have low aqueous solubility and permeability. Furthermore, Amph-B shows instability in the acidic gastric environment, which hinders its oral bioavailability [30]. The presently available formulations of Amph-B are reported for toxicities and complications including nephrotoxicity and unpredictable systemic oral bioavailability [31]. Therefore, it is necessary to design a unique formulation that could significantly improve aqueous solubility, oral bioavailability, and remarkable stability in the gastric environment, while also reducing toxicity. Herein, we synthesized a unique target oriented macrocyclic supramolecular amphiphile for the smart oral delivery of Amph-B.