Modulation of serum albumin protein corona for exploring cellular behaviors of fattigation-platform nanoparticles.

Albumin is the most abundant protein in blood, and is the most frequently identified protein in the protein corona of nanoparticles (NPs). Thus, albumin plays an important role in modulating NPs' physicochemical properties and bioavailability. In this study, the effect of bovine serum albumin (BSA) on gelatin-oleic nanoparticles' (GONs) physicochemical properties and cellular uptake were evaluated. Coumarin-6 was used as indicator to track the cellular uptake of GONs. The binding of BSA onto the GON surface increased the size, slightly reduced the negative net charge of the GON, and improved GON stability. The presence of BSA in cell culture media reduced the cellular uptake of BSA-uncoated GONs on human embryonic kidney cells 293 (HEK 293) and human adenocarcinoma alveolar basal epithelial cells (A549) in the media without FBS addition. Pre-coated BSA corona decreased cellular uptake of GONs in A549 cells in the media, with and without supplemented with 10% fetal bovine serum (FBS) but drastically increased cellular uptake on HEK 293 cells. BSA could be used to modulate protein corona as an endogenous ligand in NP design simply by mixing or incubating BSA with NPs before in vivo administration to inhibit or induce cellular uptake in specific cell types.

Design and evaluation of clickable gelatin-oleic nanoparticles using fattigation-platform for cancer therapy.

The principles of bioorthogonal click chemistry and metabolic glycoengineering were applied to produce targeted anti-cancer drug delivery via fattigation-platform-based gelatin-oleic nanoparticles. A sialic acid precursor (Ac4ManNAz) was introduced to the cell surface. Gelatin and oleic acid were conjugated by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS) chemistry with the subsequent covalent attachment of dibenzocyclooctyne (DBCO) in a click reaction on the cell surface. The physicochemical properties, drug release, in vitro cytotoxicity, and cellular uptake of DBCO-conjugated gelatin oleic nanoparticles (GON-DBCO; particle size, ∼240 nm; zeta potential, 6 mV) were evaluated. Doxorubicin (DOX) was used as a model drug and compared with the reference product, Caelyx®. A549 and MCF-7 cell lines were used for the in vitro studies. GON-DBCO showed high DOX loading and encapsulation efficiencies. In A549 cells, the IC50 value for GON-DBCO-DOX (1.29 µg/ml) was six times lower than that of Caelyx® (10.54 µg/ml); in MCF-7 cells, the IC50 values were 1.78 µg/ml and 2.84 µg/ml, respectively. Confocal microscopy confirmed the click reaction between GON-DBCO and Ac4ManNAz on the cell surface. Flow cytometry data revealed that the intracellular uptake of GON-DBCO-DOX was approximately two times greater than that of GON-DOX and Caelyx®. Thus, the newly designed GON-DBCO-DOX provided a safe and efficient drug delivery system to actively target the anticancer agents.

Fattigation-platform nanoparticles using apo-transferrin stearic acid as a core for receptor-oriented cancer targeting.

A major hurdle in cancer treatment is the precise targeting of drugs to the cancer site. As many cancer cells overexpress the transferrin receptor (TfR), the transferrin (Tf)-TfR interaction is widely exploited to target cancer cells. In this study, novel amphiphilic apo-Tf stearic acid (TfS) conjugates were prepared and characterized by Fourier transform infrared (FTIR) spectroscopy, matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry, and trinitrobenzenesulfonic acid (TNBS) assay. The prepared TfS conjugates were readily self-assembled in water to form nanoparticles (NPs), consisting of TfS as a core of NPs, whose sizes and zeta potentials were determined by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and a particle size analyzer. Hydrophilic water-soluble doxorubicin (DOX) was chosen as a model drug. DOX-loaded TfS NPs (NP+DOX), prepared by the adsorption of DOX on the NP surface via the incubation method, were analyzed for their cell targeting and killing efficiencies in TfR-overexpressing A549 and HCT116 cell lines by MTT assay, confocal microscopy, and fluorescence assisted cell sorting (flow cytometry). The data showed that NP+DOX exhibited improved cancer cell targeting and killing properties compared to that reported for free DOX. Further, the cytotoxic efficiency of NP+DOX was comparable to that of PEGylated liposomal product, Doxil®, while its cellular uptake was higher than that of Doxil®. Thus, this novel receptor-based TfS NP drug delivery system has great potential to target TfR-overexpressing cancer cells without off-target effects.

Patient-centered drug delivery and its potential applications for unmet medical needs.

Pharmaceutical dosage forms address diverse key components but satisfying unmet patient needs to enhance patient adherence is a major challenge. The desired design of patient-centered drug products should be based on characteristics of various components, such as patients, disease, routes of administration, drug delivery technologies and active pharmaceutical ingredients. Understanding of targeting patients and their physiological and biological environments is pivotal for developing suitable patient-centered drug products. In this review, key components of an ideal drug delivery system were considered. Then, stepwise approaches for designing patient-centered drug products were suggested. Finally, various case studies are also presented and considered to develop models of patient-centered drug products.

Mechanistic applications of click chemistry for pharmaceutical drug discovery and drug delivery.

The concept of click chemistry (CC), first introduced by K.B. Sharpless, has been widely adopted for use in drug discovery, novel drug delivery systems (DDS), polymer chemistry, and material sciences. In this review, we outline novel aspects of CC related to drug discovery and drug delivery, with a brief overview of molecular mechanisms underlying each click reaction commonly used by researchers, and the main patents that paved the way for further diverse medicinal applications. We also describe recent progress in drug discovery and polymeric and carbon material-based drug delivery for potential pharmaceutical applications and advancements based on the CC approach, and discuss some intrinsic limitations of this popular conjugation reaction. The use of CC is likely to significantly advance drug discovery and bioconjugation development.