Host–Guest Interactions Initiated Supramolecular Chitosan Nanogels for Selective Intracellular Drug Delivery

Abstract

Polysaccharide-based nanogels have drawn considerable interest in pharmaceutics because of their superior biocompatibility and potential responsiveness to external stimuli, enabling specific drug release. During the fabrication of nanogels, however, covalent cross-linking often involves less friendly cross-linkers and traditionally employed noncovalent cross-linking often relies on weak interactions that may lead to premature payload release. Herein, we report host–guest chemistry-driven supramolecular chitosan nanogels (CNGs) that are responsive to either endogenous or exogenous stimuli, thus allowing selective drug release in specific cancer cells or disease sites. In an aqueous solution, two phenylalanine (Phe) units of Phe-grafted chitosan (CS-Phe) were encapsulated into one cavity of cucurbit[8]­uril (CB[8]), driving cross-linking of CS-Phe and formation of CNGs. Doxorubicin hydrochloride (DOX), a chemotherapeutic agent, was entrapped in the matrix of CNGs during the formation of nanogels to yield DOX–CNGs with an excellent drug loading efficiency. The morphology and size of CNGs were fully assessed by transmission electron microscopy and dynamic light scattering. The encapsulated DOX was selectively liberated in the presence of competitive guests of CB[8], such as endogenous spermine (SPM) that is overexpressed by certain types of cancer cells or exogenous amantadine (ADA) that may be added into cells or tissues that require targeted treatment, either of which may replace Phe from the cavity of CB[8] resulting in the breakdown of the nanogels and payload release. The CNGs were efficiently internalized by cells, and the DOX–CNGs exhibited specific, potent activity against cancerous cells such as A549 cell line that is well known for SPM overexpression. This study reports that the first stimuli (competitive guest)-responsive host–guest interactions initiated supramolecular CNGs with excellent biocompatibility and selective therapeutic efficacy against cancer cells. It may provide new insights into the design and fabrication of novel stimuli-responsive payload delivery systems.

Characterization of nanoparticles combining polyamine detection with photodynamic therapy

“…According to previous studies [23][24][25] , spermine is the most abundant and representative polyamine in cancer cells. Based on a previous method 22 , the spermine determination was conducted by the HPLC method.…”

“…In addition, they trigger polyamine degradative pathways to reduce the normal polyamine content needed for cell growth. Thirdly, supramolecular traps for catching polyamines in cells have become an attractive pathway for therapeutic intervention on polyamine depletion therapy [22][23][24][25][26][27][28] . For example, Li and coworkers developed a peptide-pillar [5] arene conjugate to trap polyamines in tumor cells for suppressing tumor growth through host-guest encapsulation 22 .…”

Recent advances in polysaccharide‐based hydrogels for synthesis and applications

“…The resulting gels exhibited excellent biocompatibility and selective cytotoxicity against a therapeutic target. [ 177 ]…”

“…[23,65] Recently, this strategy was extended to prepare chitosan-based nanogels. [177] Phenylalanine (Phe) was grafted onto chitosan, in which strong inclusion complexations between CB [8] and two pendant Phe moieties facilitated the formation of nanogels. The resulting gels exhibited excellent biocompatibility and selective cytotoxicity against a therapeutic target.…”

Biowastes as a source of extracting chitin and chitosan for biomedical applications

“…, Samrot et al (2018 utilized crab shell derived chitosan for synthesis of polymeric nano particles, and these nano particles were further encapsulated with hydrophobic curcumin and analyzed for drug delivery in vitro. In 2019, hostguest chemistry-driven supramolecular chitosan nanogels were reported that were stimuli responsive thus allowing selective drug release in specific cancer cells or disease sites (Ding et al, 2019). In order to find the most suitable drug delivery system, the capacity of chitosan nanocomposite systems containing N-doped graphene or P-doped graphene nanoparticles for delivery of anticancer drug ifosfamide was examined by means of molecular dynamics simulations (Shariatinia and Mazloom-Jalali, 2019).…”