Natural biodegradable prodrug self-assembled nanoparticles for stimuli-responsive targeted anti-cancer drug delivery against multidrug resistance

Natural edible materials from plants have high potential as drug delivery carriers because of their excellent biocompatibility, biodegradability, complete non-toxicity, and zero side effects. They belong to the category that is generally recognized as safe (GRAS) by FDA, and as a drug carrier, its clinic trial can be more direct and rapid than other carriers, which is highly appreciated for drug discovery and drug delivery development. A well-selected natural edible biopolymer for drug carrier applications should own optimal chemical, biological, and morphological properties to facilitate the multifunctional drug delivery.

Cancer is one top leading cause of the deaths worldwide. The effective cancer therapy is still difficult to achieve because many problems related to general anticancer drugs, including undesirable physicochemical properties, low tumor targeting, insufficient cell internalization, acquired drug resistance, and severe side effects, have to be solved. Targeting and stimuli- responsive drug delivery system, which delivers the drug to specific tumor cells only and releases the drugs intracellularly when environmental stimuli are met, has become an important strategy to improve the efficacy of chemotherapy. Prodrug, a synthesized molecule of a drug and a carrier compound, can be designed to possess both targeting and stimuli-responsive release properties. Further, prodrugs can be designed to self-assemble into nanoparticles, which are potential to overcome multidrug resistance because of their specific endocytosis pathway, size, and surface properties.

We choose zein, an amphiphilic protein from corn, for the anticancer drug delivery nanosystem formation because of its advantages of biocompatibility, biodegradability, none water absorption, and low digestibility over other natural biopolymers. Further, it can self- assemble and be easily modified and conjugated with drugs and targeting ligands, because it contains functional groups, including many carboxyl and amine groups. We propose to use zein to make targeting ligand-conjugated prodrug self-assembled nanoparticles (TPSN) for cancer therapy. We have abundant experience on the formation and surface modification of zein self- assembled nanoparticles, and in vitro and in vivo evaluations of zein nanoencapsulations of various compounds. In this study, two model drugs, doxorubicin (DOX) and paclitaxel (PTX), and two targeting ligands (TLs), folic acid (FA) and hyaluronic acid (HA), will be selected. The TPSN will be formed in steps: (i) synthesis of zein, selected drug, and disulfide to form the prodrug (Z-prodrug), (ii) self-assembly of Z-prodrug to make nanoparticles (PSN), (iii) conjugation of TL onto PSN to form TPSN. The prepared TPSN possessed several key features, including: (i) tumor targeting via TLs; (ii) redox-responsive triggered release because of the disulfide bonds; (iii) overcoming multidrug resistance; (iv) biodegradability and biocompatibility. We will examine the in vitro targeted and triggered releases of TPSN, and study its cytotoxicity and cellular uptake and intracellular trafficking mechanisms in selected cancer cells and normal cells. We will also study the in vivo pharmacokinetics, biodistribution, and anticancer activity of TPSN using tumor xenografted animal models.