Nanostructured polymers are finding increasing use in pharmaceutical research for the development of drug delivery systems. Nano-delivery systems can be achieved with natural or synthetic polymers, however, synthetic polymers often have critical drawbacks, such as a lack of biodegradability and biocompatibility, with implications of inflammation and toxicity [1
]. In this regard, poly(glycerol adipate) (PGA) is a valid synthetic solution. PGA is an enzymatically synthesized polymer that has been shown to be a green, biodegradable, and biocompatible macromolecule. It has an amphiphilic balance within the repetitive unit that aids with the production of self-assembled nanoparticles (NPs) by nanoprecipitation in water [2
]. Moreover, the PGA suitability for drug delivery carrier development has previously been explored. For example, PGA was used as a drug delivery device of indomethacin. In particular, the polymer was grafted with the drug producing a novel composite. This grafted PGA could self-assemble into NPs and act as a drug “cargo” for a controlled delivery system [2
Oral drug delivery systems are an important strategy to achieve more effective formulations, especially those concerning poorly bioavailable drugs, such as Biopharmaceutical Classification System (BCS) class II compounds, which are defined as highly permeable but poorly aqueous soluble molecules [5
]. In this case, the role of the carrier systems is to increase the apparent water solubility of the drug in order to improve its bioavailability. This process can be limited by an earlier instability of the carrier, causing an unwanted drug precipitation in the body fluids before it can reach the proper site of absorption [6
]. The combination of nanostructured drug carriers with polymeric matrices could represent an innovative and effective approach to overcome this limitation.
Interestingly, the NPs produced with PGA show high-stability when embedded in complex polymeric semi-crystalline matrices [3
]. One example of these matrices is starch, the most abundant polysaccharide on the earth [7
]. Starch is a polymer composed of two macro-molecules: amylose and amylopectin. Amylopectin is a much larger branched polymer than amylose and represents approximately 75% of starch. Amylose instead is a linear polymer composed by α-(1-4) linked glucose units [8
]. Recently, it was demonstrated that starch is a suitable vector for the transport of PGA NPs [3
]. It was proposed that starch could trap NPs in its crystalline phase after producing the casted films, which should allow a more controlled release of a drug. Furthermore, starch films produced with and without NPs stimulated the growth of intestinal cells.
For all these reasons, we sought to develop a novel oral drug delivery system consisting of native barley starch blended with PGA NPs in order to obtain a biocompatible nanocomposite to improve the apparent water solubility of drugs.
Kinase inhibitors (KIs) are a class of drugs whose application in cancer treatment is constantly growing. Indeed, 49 KIs have been approved by the FDA over the last 20 years [11
] and more than 2000 clinical trials evaluating these compounds are ongoing [13
]. KIs, blocking specific enzymatic pathways that are hyper activated in tumors, have paved the way for better tolerated and targeted cancer therapies [14
]. Although small molecule KIs can generally be orally administered [12
] with remarkable advantages for patient treatment, they are often affected by a poor pharmacokinetic profile. This can lead to variations in plasma concentration, insufficient levels of the drug at the site of action, variability in systemic response, and other hardly controllable answers that can compromise the efficacy of therapy [15
]. For these reasons, many strategies, such as the preparation of prodrugs, polymeric NPs, or liposomes, have been already developed or are under investigation in order to overcome this KI intrinsic limit [16
Schenone et al. have reported a wide library of potent KIs endowed with a pyrazolo[3,4-d
]pyrimidine scaffold [17
]. Many of these compounds are active on different cancer cell lines, and some also showed activity in in vivo mouse models [19
]. Among the members of this library, compound SI214 (Figure 1
a) is a potent Src inhibitor (Ki
= 90 nM) and possesses a considerable antiproliferative effect on the SH-SY5Y Neuroblastoma cell line (IC50
= 80 nM). Despite these promising biological data, SI214 has low solubility in water (0.12 g/mL), which prevents its oral administration [21
]. It has been successfully demonstrated that solid dispersions of pyrazolo[3,4-d
]pyrimidine analogous containing an hydrophilic polymer as inert carrier possess an increased apparent water solubility due to enhanced interactions between the hydrophilic polymeric chain and the hydrophobic drug scaffold leading. It was further shown that the polymer–drug interactions led to the nano-microaggregates of the formulations assembling themselves [22
]. For this reason, we selected SI214, as a pyrazolo[3,4-d
]pyrimidine model, for the following study.
Furthermore, evidence shows that the pyrazolo[3,4-d
]pyrimidine nucleus can be a valuable scaffold to develop antimicrobial agents [23
] and thus we additionally evaluated this compound against a series of strains of S. aureus
and E. coli
To further validate our work, we extended the in vitro evaluation to Camptothecin (CPT) (Figure 1
a), a topoisomerase I inhibitor, whose activity as anticancer agent is confirmed [26
] and efficacy as antimicrobial drug has been recently investigated [27
]. CPT, as with SI214, suffers from low solubility in water and, in addition, is characterized by poor stability [28
Therefore, in the present study, starch/PGA nanocomposites were characterized for the oral drug-delivery of SI214 and CPT molecules as anticancer and antimicrobial agents. A systematic study of encapsulation, via solubility enhancement UV-vis evaluation, was performed and showed that the NPs increased the apparent solubility in water of the drugs of several order of magnitudes compared to the pure drugs. Then, the stability profile of starch-NP nanocomposites was evaluated upon exposure to conditions mimicking the human gastrointestinal (GI) environment: the PGA was grafted with a fluorophore (Cy5) and the NP release from the matrix starch was monitored in a dynamic in vitro model simulating the human digestion. The formulations tuned the release of the NPs, demonstrating the feasibility of our novel system as an edible nanocomposite.