**Polymeric carriers**


**Figure 4.** Shows the formation of chitosan nanoparticles modified with tripolyphosphate (TPP)-loaded letrozole [52]. Copyright ©2017, Elsevier.

The use of chitosan nanoparticles was reported by Wang et al., in 2017, for insulin delivery [53]. Zhang et al. modified chitosan by using heptamethine and folate for photodynamic treatment and tumor-imaging [54]. Kamel et al. modified chitosan by encapsulating oregano and cinnamon within

chitosan in combination with 5-fluorouracil as an effective agent for tumors [55]. Lin et al. studied chitosan derivatives and found that chitosan-based nanocarriers used for co-delivery of genes and drugs were redox responsive [56]. In 2017, Gu et al. reported antibody modified nanoparticles. The delivery of drugs to the brain has always been a challenging task because the blood–brain barrier does not allow quick cellular uptake to the brain [57]. Auspicious work has been done by Par et al. for cancer treatment; the authors used glycol-modified chitosan nanoparticles for the effective release of doxorubicin [58]. In 2018, Belbekhouche et al. synthesized chitosan/polyacrylic modified nanoparticles for drug delivery systems [59]. A considerable amount of experimental work has been reported by Bernkop-Schnürch et al. [41]. The authors studied the efficiency of chitosan for different drug delivery systems: oral, gastric (for cancer treatment), nasal, buccal, intravesical, ocular, and, additionally, systems for vaccine delivery. The properties of chitosan nanoparticles vary when coupled with a hydrophilic polymer. This modified form of chitosan has shown novel susceptibility for delivering protein and interaction with the biological surface [43]. Calvo et al. examined the remarkable properties of modified chitosan using the diblock copolymer of ethylene oxide and propylene oxide as a protein carrier. The introduction of a PEG coating on the surface of chitosan decreases its cationic surface charge and, remarkably, increases its biocompatibility [60].

In 2002, Shu and Zhu [61] studied the effect of electrostatic interaction on properties of chitosan ionically crosslinked with multivalent phosphates such as tripolyphosphate, phosphate and pyrophosphate. Chitosan cross-link ionically due to the greater negative charge on the surface of phosphates. The solution pH plays a vital role in electrostatic interaction between chitosan and multivalent phosphates. Pyrophosphate/chitosan exhibits greater interaction as compared to other tripolyphosphates and phosphates. Ionically cross-linked chitosan and tripolyphosphates displayed better surface charge to size ratio for particles and showed better association with vaccines, proteins, plasmids, peptides, and oligonucleotides [61]. Recently many issues related to cancer treatment, such as hematogenous metastasis, drug resistance and local reappearance have led to the failure of treatment methods [62]. The main problem related to cancer treatment is finding a drug delivery system that fits the requirements. Shafabakhsh et al. [38] reported a review of gastric cancer treatment using chitosan nanoparticles. The authors investigated the effect of the anticancer drug norcantharidin conjugated with carboxymethyl modified chitosan.

In comparison with the simple drug, the carboxymethyl/chitosan encapsulated the drug successfully and suppressed the migration and proliferation of gastric cancer cells. This study reported that carboxymethyl chitosan could increase gene expression and may provide a favorable drug delivery system for gastric cancer treatments [38,63]. Moreover, chitosan nanoparticles used for the treatment of H. pylori infection have been shown to improve the effect of amoxicillin; chitosan nanoparticles improve the release time of the drug by preventing them from enzymatic and acidic breakdown through bonding to the mucus barrier of the stomach and drug release into the mucus barrier, thus leading to greater efficacy at the infected site [64,65].

Øilo et al. [66] suggested dental coating by using modified chitosan with other alternative antibacterial agents. The formation of biofilms causes common dental diseases that involve microbes adhering to teeth or restorative materials. Microbial adhesion is followed by bacterial growth and colonization, resulting in the formation of a compact biofilm matrix [67]. This matrix protects the underlying bacteria from the action of antibiotics and host defense mechanisms. The biofilm formed on teeth, prostheses, or implant-anchored restorations contains aciduric organisms such as *Streptococcus mutans* (*S. mutans*) and *lactobacilli* that secrete acid causing enamel and dentin demineralization. Biofilm formation on dental implants can result in a severe infection leading to dental implant failure. The formation of biofilm is reduced by different antibacterial agents such as quaternary ammonium compounds [68], inorganic nanoparticles [69], or fluoride varnish with natural products [70], which are used in the dental materials. Dental varnishes containing fluoride with natural products such as chitosan are a practical approach. Newer techniques include the use of an antibacterial polymer coating drug delivery system to prevent bacterial growth on artificial tooth surfaces in other dental materials and dental composite kits, increasing the longevity of the dental restoration [71]. Examples of such antibacterial coatings include copolymers of acrylic acid, alkyl methacrylate, and polydimethylsiloxane copolymers [72], pectin coated liposomes, and carbopol [73].
