br Introduction br Lung cancer is a severe illness derived
Lung cancer is a severe illness derived from malignant tumor de-veloped in the respiratory epithelium (bronchi, bronchioles, and al-veoli)  and in 2018 it was marked as the most common cancer worldwide (2.09 million cases), having the greatest number of cancer deaths (1.76 million deaths), according to WHO (World Health Orga-nization) . Even though it is more frequent in men, in recent years an alarming increase in the incidence rate in women has been reported . In addition, a five-year survival rate of 18.6%, is much lower than other common cancer, such as colorectal (64.5%), breast (89.6%) and pros-tate (98.2%) .
The standard protocol for the treatment of lung cancer includes surgery (complex operation), radiotherapy and chemotherapy, de-pending on the cancer stage, overall health, and lung function ; being the chemotherapy the most frequently used . The
chemotherapeutic drugs also act on normal cells, inhibiting their growth; this makes the patient extremely weak and can result in death .
After 40 years since U.S. FDA approved cis-diaminodi-chloroplatinum (II) (CDDP, known also as cisplatin) for medical treat-ment, it is still widely used in the chemotherapy of diﬀerent solid tu-mors including lung cancer, gastrointestinal, and genitourinary. CDDP-based chemotherapy is accepted as a standard first-line treatment for advanced non-small cell lung carcinoma (NSCLC) [7–9]. The high ef-ficiency is due to its characteristic of an eﬀective chelating agent of DNA. However, its clinical application has been limited due to severe side eﬀects, among the most frequent ones are the chronic damage to the SB-203580 and short- and medium-term sequelae have been seen in the liver and kidney and serious aﬀectations, also ne-phrotoxicity and hepatotoxicity have been generated in long-term periods [10–12].
Corresponding authors at: Tecnológico Nacional de México/Instituto Tecnológico de Tijuana, Centro de Graduados e Investigación en Química, Blvd. Alberto Limón Padilla S/N, Fracc. Otay-Tecnológicos, C.P. 22500 Tijuana, B.C., Mexico. E-mail addresses: [email protected], [email protected] (I. Zapata-Gonzalez), [email protected] (A. Licea-Claverie).
Recently, medical sciences are changing the focus towards the de-velopment of multifunctional drug delivery systems at the nanometer scale [13,14]. The most promising alternative to increase the drug se-lectivity is its encapsulation in biocompatible nanogels, in order to re-duce the side eﬀects of the drugs [15–17]. A fundamental characteristic in the microenvironment of tumor tissue is the lower pH level than in the normal tissue (7.4), due to this, pH-sensitive nanogels are potential candidates for drug delivery into tumors [18–20]. Recently, it has been demonstrated that surface charge and particle size of nanoparticles are one of the most determinant parameters for endocytosis, in addition to other chemical characteristics, such as composition [21–23].
In general, considering pH-dependent surface charge in the design of nanogels, two types of nanogels can be envisioned in order to reach a high loading and a controlled release of cisplatin: a) anionic nanogels (AN) (COOH containing polymers), able to promote a chelating ligand-metal coordination between the acid monomeric units and CDDP, and
b) cationic nanogels (CN) (N-containing polymers), able to form in-termolecular interactions between the drug and the functional groups of the polymer or also ligand-metal coordination.
With respect to AN, a great number of studies about anionic nano-particles and their complex formation with CDDP have been reported. ANs showed high eﬃciencies and capacities in loading and a good re-lease behavior of CDDP. Biocompatibility tests suggested that the toxic side eﬀects of CDDP could be diminished greatly via Pt directed co-ordination-crosslinking with COOH-containing ANs . In fact, the nature of the metal-ligand coordinated bond is a key point in the design of AN. According to Ohta et al. , a higher number of members in the metal-ligand coordination (formed between the AN and the CDDP) re-sulted in stronger stability, benefiting the drug loading. However, the amount of CDDP released was aﬀected with respect to the complex stability and the cell viability followed the same tendency. Instead, the strong stability of the formed metal-ligand complex could prejudice the ANs performance against other loading principles; for instance, nano-gels of poly(ethylene oxide)-b-poly(methacrylic acid) were conjugated to folic acid (FA-nanogels) and loaded with CDDP or doxorubicin (DOX), loading capacity was higher for DOX than CDDP in the FA-na-nogels, and the DOX release rate was faster than that exhibited in the CDDP-loaded nanogels. This behavior was attributed to the stronger coordination bonding between Pt and COOH groups of the ANs, as compared with electrostatic coupling in the case of DOX-loaded nano-gels . Other reports taking advantage of complex formation be-tween COOH groups and Pt of CDDP comprise malonic acid , glutamic acid , lactic acid , and glycolic acid  as ligands.