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Quetiapine myristate (QM), an ester-bonded lipophilic prodrug of quetiapine (QTP), is synthesized and converted into an amphiphilic structure in acidic pH to trigger a novel self-assembled QM nanosuspension (QMN). Following injection, this QMN rearranges within physiological pH to form nanoaggregates in structure, resulting in enhanced physicochemical properties and in vivo therapeutic performance without an initial burst release. The 200-nm-sized QMN exhibits less invasive injection, higher drug content, and better storage stability profile than conventional poly(lactide-co-glycolide) (PLGA) nanosuspensions containing QTP or QM. Following a single intramuscular injection to beagle dogs (35 mg kg -1 QTP), QMN undergoes pH-responsive nanoaggregation to form the lipophilic prodrug, providing esterase-oriented sustained release for five weeks compared with the two-week period of PLGA nanosuspensions. Notably, QMN exhibits improved in vivo pharmacokinetic performance with long-acting delivery while minimizing issues associated with polymeric PLGA formulations, including the initial massive burst release, cellular toxicity, and adverse side effects. These results support the further development of QMN as a novel long-acting injectable to improve patient compliance and dosing frequency., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The aim of this study was to evaluate the enhanced thermal stability and physicochemical properties of fattigated vaccine antigens. High molecular weight influenza hemagglutinin (Heg) was used as a model antigen because of low heat stability requiring cold chamber. Heg was conjugated with long-chain oleic acid (C18) and short-chain 3-decenoic acid (C10) to prepare fattigated Heg. Circular dichroism analysis revealed no significant changes in the three-dimensional structure post-conjugation. In the liquid state, the fattigated Heg was self-assembled into nanoparticles (NPs) due to its amphiphilic nature, with sizes of 136.27 ± 12.78 nm for oleic acid-conjugated Heg (HOC) and 88.73 ± 3.27 nm for 3-decenoic acid-conjugated Heg (HDC). Accelerated thermal stability studies at 60 °C for 7 days demonstrated that fattigated Heg exhibited higher thermal stability than Heg in various liquid or solid states. The longer-chained HOC showed better thermal stability than HDC in the liquid state, attributed to increased hydrophobic interactions during self-assembly. In bio-mimicking liquid states at 37 °C, HOC exhibited higher thermal stability than Heg. Furthermore, solid-state HOC with cryoprotectants (trehalose, mannitol, and Tween® 80) had significantly increased thermal stability due to reduced exposure of protein surface area via nanonization behavior. The current fattigation platform could be a promising strategy for developing thermostable nano vaccines of heat-labile vaccine antigens., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: To conjugate different degree of saturation of C18 fatty acids (stearic acid, oleic acid, and linoleic acid) with the hydroxyl groups of leuprolide acetate (LEU acetate) and to investigate the controlled release and enhanced permeability through self-assembled nanoparticles (L18FNs)., Methods: Yamaguchi esterification with benzoyl chloride and DMAP (4-Dimethylaminopyridine) allowed the conjugation of the fatty acid to the hydroxyl group of LEU. The three conjugates were then designated as stearic acid-conjugated LEU, LSC, oleic acid-conjugated LEU, LOC, and linoleic acid-conjugated LEU, LLC, respectively. The conjugates (L18FCs) were purified using preparative HPLC (Prep-HPLC) and identified through various instrumental analyses., Results: The zeta potential, particle size, and morphology of each L18FNs were evaluated. In the case of LSNs, the zeta potential value was relatively low and the particle size was larger than LONs and LLNs owing to the higher hydrophobicity of saturated fatty chain, while the LLNs showed a higher zeta potential and smaller particle size. In human plasma, LLC showed the fastest degradation rate with the highest accumulative drug release. The permeability of L18FNs was analyzed through the Franz diffusion cell experiment, confirming that the degree of saturation of fatty acids affects the permeability of LFNs. While the permeability of LSNs was not significantly enhanced due to higher particle size after nanonization, LONs and LLNs increased 1.56 and 1.85 times in permeation, respectively, compared to LEU., Conclusion: Utilization of different degree of saturation of fatty acids to conjugate a peptide drug could provide pharmaceutical versatility via self-assembly and modification of physicochemical properties., Competing Interests: Kye Wan Lee reports grants from Ministry of Trade, Industry & Energy (MOTIE, Korea), during the conduct of the study, and is an employee of Dongkook Pharmaceutical Co., Ltd, Seoul, Republic of Korea. The authors report no other potential conflicts of interest in relation to this work and declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (© 2022 Park et al.)

Purpose: To investigate the effects of solvents on the formation of self-assembled nanonization of albumin-oleic acid conjugates (AOCs) using a solvent exchange mechanism for the construction of in situ forming implants (ISFI)., Methods: A poorly water-soluble drug, paliperidone palmitate (PPP), was chosen as the model drug. AOC was synthesized with the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) reaction. Dichloromethane, tetrahydrofuran, ethanol, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and deionized water were selected to investigate the formation of self-assembled AOC nanoparticles (AONs). The volume ratios of organic solvents against water could determine the miscibility, injectability, and in situ nanonizing capability without aggregation., Results: As the polarity of the organic solvents increased, the AONs exhibited a spherical shape, and the larger the volume of the solvent, the smaller the size of the AONs. To use AOC in ISFI for controlled release of PPP, poly(d,l-lactide-co-glycolide) (PLGA) was combined with the AOC in 2 mL of N-methyl-2-pyrrolidone and water solution (1.8/0.2 ratio). The release rates of all formulations exhibited similar curve patterns overall but were more controlled in decreasing order as follows: AOC, PLGA, and AOC/PLGA for 14 days., Conclusion: A combined formulation of AOC and PLGA was found to effectively control the initial burst release of the drug., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this study., (© 2021 Yu et al.)

An acid-base neutralization technique has generated interest for the ability to achieve an enhanced dissolution of pH-dependent weakly basic or acidic poorly water-soluble drugs. However, the underlying nanonization mechanism, following acid-base neutralization, requires further elucidation. We hypothesized that the nanosuspensions (NSPs) via nanonization of drug particles could be attributed to the "salt-induced effect" and surfactant-driven micellization after acid-base neutralization. Rebamipide (RBM) and valsartan (VAL) were chosen as model drugs owing to poor water solubility and pH-dependent aqueous solubility. The drug NSP was rapidly obtained via salt formation (NaCl) after neutralization of the drug in basic NaOH solution and poloxamer 407 (POX 407) in acidic HCl solution. The NSP surrounded by NaCl salt was further stabilized by POX 407. The resulting NaCl salt modulated the critical micelle aggregation of POX 407, stabilizing the drug-loaded NSP in a cage of salt and micellar surfactant. In non-assisted homogenization, size analysis indicated the relationship between salt concentration and size reduction. Fourier transform infrared (FTIR) spectra revealed that the existence of hydrogen bonding between the drug and surfactant after neutralization, attributed to NSP size reduction. Changes in drug crystallinity to the nano-amorphous state were confirmed by powder X-ray diffraction (PXRD). Overall, the salt-induced drug NSP synergistically enhanced the dissolution rate, narrowing a gap between drug dissolution profiles in different pH environments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aims of this study were to design different chain length fatty acid-conjugated albumin nanoparticles (ANPs) and evaluate their anticancer activity in the HCT116 human colorectal cancer xenograft mouse model. Doxorubicin hydrochloride (DOX·HCl) was chosen as a model drug. The different chain lengths of fatty acids (butyric acid; C4, and stearic acid; C18) in albumin conjugates exhibited different physicochemical properties and anticancer activity. Fatty acid-conjugated albumin aided the formation of self-assembled structures with an average size of approximately 200 nm and a negative charge when incubated with excess DOX in an aqueous solution. DOX-loaded long-chain C18-conjugated ANPs allowed efficient encapsulation of hydrophobic DOX into the core of the self-assembled structure, enabling higher drug loading, enhanced colloidal stability and controlled release behavior in PBS pH 7.4 medium as compared with free DOX·HCl or non-fatty acid conjugated ANPs. Furthermore, DOX-loaded fatty acid-conjugated ANPs showed an increased cellular uptake intensity and cytotoxic effects in vitro. In vivo, HCT116 xenograft model experiments confirmed that DOX-loaded C18-conjugated ANPs showed improved anticancer activity and reduced side effects compared with the DOX-treated groups. The long-chain fatty acid-conjugated ANPs synergistically activated the interaction with the free-fatty acid receptor (FFAR) on HCT116 colorectal cancer cells as compared with short-chain C4 or other non-conjugated ANPs. Specifically, DOX-loaded C18-conjugated NPs exhibited significant performance to overexpressed FFAR4 on HCT116 colorectal cancer cells. The fatty acid chain length in the fattigation-platform system could be a promising molecular moiety to improve targeting efficiency and drug accumulation in various cancer therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This study aimed to design the ideal nanonizing vehicle for poorly water-soluble model curcumin (CCM) using fattigation-platform nanotechnology, and to investigate the effects of fatty acid salts chain length on nanonizing CCM and its efficient delivery to different cancer cells. HSA-fatty acid conjugates were synthesized by EDC/NHS coupling. Fattigation-platform nanomicelles (NMs), prepared by film hydration, exhibited uniform and spherical morphology, although, each NM varied in particle size, zeta potential, and critical micelle concentration according to the types of fatty acid. Preliminary solubility studies of albumin conjugates with 5 types of fatty acid salts of different chain lengths revealed that C14 exhibited the highest solubilization of CCM. CCM-loaded HSA-C14 NMs demonstrated the highest drug content (5.35 ± 0.48%) and loading efficiency (95.93 ± 1.87%) compared to other NMs. It exhibited enhanced drug release rate and reduced micelle size in biorelevant dissolution medium. Interestingly, this solubilization approach was well applied in poorly water-soluble docetaxel trihydrate (DTX). Preliminary solubility results of DTX was also corresponded to the stable nanonization phenomenon in biorelevant dissolution medium. Compared to the CCM EtOH solution, HSA-C14 NMs showed higher internalization in cancer cell lines A549 and MCF-7, and consequently, exhibited significantly increased cytotoxicity against both cell lines. Therefore, this study provides a new solubilization approach for poorly water-soluble drugs using fatty acid salts of different chain lengths and their micellar formations via nanonization, which could be a promising tool for targeted cancer therapy using poorly water-soluble drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Nanoparticle-protein interactions under conditions mimicking physiology determine how nanoparticles (NPs) will behave inside blood vessels and, therefore, the overall outcome of the drug-delivery system. Here, for the first time, we explore the effects of bio-mimicking shear stress and protein corona conditions on novel active targeting of clickable fattigation nanoparticles (NPs) for cancer therapy. Active targeting dibenzocyclooctyne-functionalized biocompatible gelatin-oleic NPs (GON-DBCOs) via a bioorthogonal click reaction were prepared by the desolvation method for delivery of docetaxel (DTX) to lung and breast cancer models. The effect of shear stress (5 dyne/cm 2 ) and human serum albumin (HSA) protein corona on the cellular behavior of NPs was explored under a dynamic microfluidic system in lung (A549) and breast (MCF-7) cancer cell lines. The developed drug-loaded NPs had a particle size of 300 nm, a narrow size distribution, positive zeta potential, high encapsulation efficacy (72.4%), and spherical morphology. The particle size of the protein corona-coated NPs increased to 341 nm with a negative zeta potential. The inhibitory dose (IC 50 ) increased approximately 3- and 42-fold in A549 and MCF-7 cells, respectively, under dynamic microfluidic conditions compared to static conditions. Cellular uptake was significantly decreased in the presence of shear stress and a protein corona, compared with static conditions, in both lung (A549, **p < 0.01) and breast (MCF-7, *p < 0.05) cancer cell lines. Clathrin-and energy-dependent pathways were found to be involved in the cellular uptake of NPs. This study could serve as a vital tool for the evaluation of NPs under aggressive bio-mimicking conditions comprising shear stress and a protein corona to predict the in vivo performance of NPs and support the preclinical and clinical translation of NP drug delivery systems., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Solubilizing adjuvants are commonly used to dissolve insoluble drugs by simply adding in a formulation. In this study, gelatin and oleic acid sodium salt (OAS), a generally recognized as safe-listed material were chosen and conjugated to develop a natural solubilizing adjuvant using the fattigation platform technology to enhance solubility and dissolution rate of poorly water-soluble drugs according to self-assembly and nanonization principle when simply mixed with poorly water-soluble drugs. We synthesized the gelatin and OAS conjugates (GOC) at three different ratios (1:1, 1:3, 1:5; GOC 1, GOC 2, and GOC 3, respectively) via the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide reaction using a spray dryer. This amphiphilic micronized GOC was self-assembled into nanoparticles. The synthesis of new amphiphilic conjugates was identified through Fourier transform-infrared (FT-IR) spectroscopy. The powder properties of the GOCs, such as angle of repose, bulk density, and tapped density were varied with the oleic acid bonding ratio. Then, GOCs were utilized to investigate the enhanced solubility and release rate of various poorly water-soluble drugs such as cilostazol (CSZ), coenzyme Q10, ticagrelor, telmisartan, aprepitant and itraconazole as model drugs. Based on the solubility studies by concentration and type of GOCs, 3% GOC 2 was selected. When this GOC was mixed with these model drugs by the physical mixing, wetting and hot melting methoods, the solubility was highly enhanced compared to the pure control drug, ranging from 20 to 150,000 times. In case of CSZ, all formulations were significantly improved release rate compared to the of CSZ alone and the reference tablet, cilostan® (Korea United Pharm) in simulated intestinal fluid containing 0.2% sodium lauryl sulfate. Differential scanning calorimetry and powder X-ray diffraction were conducted to confirm the crystal polymorphic structure of CSZ, and as a result they changed to diminutive peak intensity compared to CSZ alone. Field-emission scanning electron microscopy indicated that GOC was round with a reduced size of about 100 nm. The reduction of drug particles via nanonization and self-assembly of amphiphilic GOC in an aqueous media could be a key factor to improve poor water solubility by providing a favorable dispersion of drug molecules in an amphiphilic network., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Extracellular vesicles have an excellent ability to transfer their contents to cells. Extracellular vesicles can also be engineered to deliver therapeutic molecules to target cells. Although a number of studies have exploited synthesized nanoparticles in the treatment of neurological disease in the past few years, extracellular vesicles have been investigated and shown tremendous promise for clinical applications because they are safe and have strong targeting specificity. Different types of extracellular vesicles have been studied and modified for delivering therapeutic factors in neurological disease, including extracellular vesicles loaded with natural therapeutic factors and therapeutic molecules. In this review, we discuss delivery systems using extracellular vesicles containing molecules of interest and then focus on main strategies used for EV loading and surface modification. Discussing these important issues will support and facilitate the design and development of promising techniques and products for neurological therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The long history of discovery and recently encouraging studies of the anti-cancer effect of aspirin promise a closer step to widely used aspirin-based medication in cancer therapy. To resolve the poor water-solubility of aspirin and low encapsulation efficiency of exosomes for further developing a new delivery of aspirin as anti-cancer treatment, our nanoamorphous exosomal delivery platform was established. In this study, the anti-tumour effects of nanoamorphous aspirin-loaded exosomes with exosomes derived from breast and colorectal cancer cells, were comprehensively studied using both in vitro and in vivo models. These exosomes displayed enhanced cellular uptake via both clathrin-dependent and -independent endocytosis pathways, and significantly improved cytotoxicity of aspirin to breast and colorectal cancer cells, accompanied by the enhanced apoptosis and autophagy. Remarkably, this nanoamorphous exosomal platform endowed aspirin with the unprecedented cancer stem cell eradication capacity. Further animal study demonstrated that this developed exosomal system was able to efficiently deliver aspirin to in vivo tumours. The active targeting of these exosomes to tumour was further improved by conjugating an aptamer specifically targeting EpCAM protein. Hence, this nanoamorphous structured exosome system effectively transformed aspirin into a potential cancer stem cell killer with distinguished properties for clinical translation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Despite several studies on film-forming systems with the advantages of both the film and the hydrogel, there are still no effective systems for fast film formation with a high level of control over permeability. In this study, a film-forming system for the delivery of nanomedicine, termed a film-forming nanogel (FFN), was produced and investigated for the first time to meet this need. The objective of this research was to study a new generation of film-forming hydrogels (FFHs) loaded with curcumin nanoparticles (CUR-GNPs) for transdermal applications. FFHs were prepared by employing zein and HPMC 4000 as film-forming polymers. Meanwhile, CUR-GNPs were obtained by sonoprecipitation. The film-forming time, particle characteristics and FFN drug release profile were assessed. The optimized FFH had a smooth surface and a fast drying time of 6 min and 4.5 min in vitro and ex vivo, respectively. Additionally, high, sustained drug permeation from the FFN was observed after 24 h. The FFH containing CUR-GNPs showed potential for application in transdermal drug delivery with a fast film-forming time, uniform particle dispersion and high, sustained drug permeation.

The aim of this study was to investigate the impact of different chain length fatty acids on physicochemical properties and cancer targeting of fattigation-platform nanoparticles (NPs). Two different types of fatty acids (short chain, 2-hydroxybutyric acid, C4; long chain, oleic acid, C18:1) were successfully conjugated to human serum albumin (HSA) via simple 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) coupling reaction. These conjugates readily formed HSA-C4 and HSA-C18:1 NPs which showed good stability in serum and desirable biocompatibility with normal cell line (HEK293T). Doxorubicin hydrochloride (DOX) was efficiently loaded into NPs by incubation process via electrostatic interaction. The structure, morphology, and texture of DOX-loaded NPs were characterized by Transmission electron microscopy (TEM) equipped with Energy-dispersive X-ray spectroscopy (EDS). The initial burst release of DOX-loaded NPs was controlled by the presence and chain length of fatty acids. In vitro cytotoxicity studies with three cancer cell lines (A549, HT-29, and PANC-1) suggested that fattigation-platform NPs have distinctive cytotoxic effects compared to Doxil ® . Confocal microscopy and flow cytometry exhibited that the cellular uptake of DOX-loaded NPs was varied by the different chain lengths of fatty acids. It was evident that the chain length of fatty acids in the fattigation-platform NPs could play a vital role in varying physicochemical properties and cancer cell targeting of NPs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Recently, several strategies have been proposed for skin cancer therapy by transdermal delivery, and particularly the use of nanotechnology., Methods: This process disrupts the stratum corneum to deliver a drug through the skin, allowing it to accumulate at the tumor site., Results: Nanogels are drug delivery systems that can be applied to many diseases. Nanogel engineering has been widely studied for use in drug delivery, particularly in cancer theranostics. This review summarizes specific strategies for using nanogels to treat skin cancer, a topic that is limited in recent literature., Conclusion: Advanced techniques for effective skin cancer therapy based on the nanogel's penetration and cellular uptake abilities will be discussed. Moreover, techniques for penetrating the skin, as well as drug release, permeation studies, and microscopic observations, will also be discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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 (Ac 4 ManNAz) 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The aim of this research was to engineer solid dispersion lipid particles (SDSLs) in which a solid dispersion (SD) was encapsulated to form the core of solid lipid particles (SLs), thereby achieving an efficient enhancement in the dissolution of a poorly water-soluble drug., Methods: Ultrasonication was introduced into the process to obtain micro/nanoscale SLs. The mechanism of dissolution enhancement was investigated by analysing the crystalline structure, molecular interactions, and particle size of the formulations., Results: The drug release from the SD-SLs was significantly greater than that from the SD or SLs alone. This enhancement in drug release was dependent on the preparation method and the drug-topolymer ratio of the SD. With an appropriate amount of polymer in the SD, the solidification method had the potential to alter the drug crystallinity to an amorphous state, resulting in particle uniformity and molecular interactions in the SD-SLs., Conclusions: The proposed system provides a new strategy for enhancing the dissolution rate of poorly water-soluble drugs and further improving their bioavailability., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This study was aimed at characterizing superparamagnetic nanoparticles surface-functionalized with gelatin-oleic acid (GOAS-MNPs) and loaded with paclitaxel by assessing the pharmacokinetics and biodistribution of paclitaxel in tissues and the in vivo efficacy of antitumor activity after the administration of the drug. Initially, instrumental analysis was performed to examine the particle size distribution, surface charge, and morphology of the paclitaxel-loaded GOAS-MNPs. Furthermore, we evaluated their magnetic properties and performed T2-weighted magnetic resonance imaging (MRI) on cells. We intravenously administered Taxol® and paclitaxel-loaded GOAS-MNPs and compared the pharmacokinetics, biodistribution, and antitumor efficacies of the two formulations. Determination of the pharmacokinetics and the biodistribution of paclitaxel-loaded NPs showed that this formulation increased the systemic circulation time of paclitaxel and regulated its transport to tissues. The in vivo antitumor efficacy of the paclitaxel-loaded NPs was better than that of Taxol® at the same dose. Furthermore, the paclitaxel-loaded GOAS-MNPs were found to be effective as contrast agents for enhanced MRI in cancer cells. Thus, GOAS-MNPs could be an effective diagnostic system for cancer and for the delivery of paclitaxel with better therapeutic effects and a significant reduction in toxicity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

After administration of nanoparticle (NP) into biological fluids, an NP-protein complex is formed, which represents the "true identity" of NP in our body. Hence, protein-NP interaction should be carefully investigated to predict and control the fate of NPs or drug-loaded NPs, including systemic circulation, biodistribution, and bioavailability. In this review, we mainly focus on the formation of protein corona and its potential applications in pharmaceutical sciences such as prediction modeling based on NP-adsorbed proteins, usage of active proteins for modifying NP to achieve toxicity reduction, circulation time enhancement, and targeting effect. Validated correlative models for NP biological responses mainly based on protein corona fingerprints of NPs are more highly accurate than the models solely set up from NP properties. Based on these models, effectiveness as well as the toxicity of NPs can be predicted without in vivo tests, while novel cell receptors could be identified from prominent proteins which play important key roles in the models. The ungoverned protein adsorption onto NPs may have generally negative effects such as rapid clearance from the bloodstream, hindrance of targeting capacity, and induction of toxicity. In contrast, controlling protein adsorption by modifying NPs with diverse functional proteins or tailoring appropriate NPs which favor selective endogenous peptides and proteins will bring promising therapeutic benefits in drug delivery and targeted cancer treatment., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Cancer cells in the tumor microenvironment are affected by fluid shear stress generated by blood flow in the vascular microenvironment and interstitial flows in the tumor microenvironment. Thus, we investigated how fluidic shear stress affects cellular uptake as well as the endocytosis mechanism of nanoparticles using a biomimetic microfluidic system that mimics the human dynamic environment. Positively charged amino-modified polystyrene nanoparticles (PSNs) at 100 μg/mL were delivered to cancer cells under static and biomimetic dynamic conditions (0.5 dyne/cm 2 ). Additionally, the experiment was done in the presence of endocytosis inhibitors specific for one of the endocytosis pathways. To evaluate cellular uptake of cationic PSNs, the fluorescence intensity of cationic PSNs in cancer cells was measured by flow cytometer and fluorescence images were taken using confocal laser scanning microscopy. Cancer cells in dynamic conditions exhibited higher cellular uptake of PSNs and showed different cellular uptake mechanisms compared with those in static conditions. From these results, it suggested that biomimetic dynamic conditions stimulated specific endocytosis and prompted cellular uptake. It was also important to consider fluidic shear stress as one of the critical factors because cellular uptake and drug delivery could play a key role in cancer cells and metastasis.

This study was aimed at achieving enhanced solubility of aceclofenac (ACF) in nanocrystaline forms (ACF-NC) and evaluating the effects of ACF-NC on cell viability. Decorated ACF-NC were prepared by nano-precipitation with stabilizers. Three kinds of stabilizers were investigated: Tween 80, Poloxamer 407, and PEG 6000. The crystal structure and morphology of ACF-NC were characterized by field emission scanning electron microscopy (FE-SEM) and differential scanning calorimetry (DSC). The solubility of ACF-NC and ACF (pure) was evaluated in different media (pH 1.2 and pH 6.8 buffers and distilled water [DW]). A drug release study was performed in PBS for 24h. Cell viability was evaluated for 24h using a human colon cancer cell-line (HCT-116) and a human breast cancer cell-line (MCF-7). Decorated ACF-NC with a mean size of 725nm were successfully prepared. The solubility of the decorated ACF-NC were 4-7 times higher than that of ACF in DW and pH 6.8 buffer. A peak shift from 153.1°C to 150.5-151.0°C was observed in the DSC thermogram of decorated ACF-NC versus ACF. In terms of drug release, there was an initial burst in decorated ACF-NC within 1h followed by slow release for up to 4h. Decorated ACF-NC exhibited viability approximately 63.9% of HCT-116 cells and also showed viability in 58.3% of MCF-7 cells at 15μg/mL of drug concentration. In conclusion, decorated ACF-NC proved to be a promising approach for enhancing drug solubility and cytotoxicity., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In this study, we investigated a new method for the preparation of gelatin-oleic conjugate (GOC) as an amphiphilic biomaterial to load model anti-cancer drugs into self-assembled nanoparticles (NPs). Oleic acid (OA) was covalently bound to gelatin via carbodiimide/N-hydroxysuccinimide (EDC/NHS) reaction in water-ethanol cosolvent to form a GOC. Fourier transform infrared (FT-IR) spectroscopy and proton nuclear magnetic resonance ((1)H NMR) clearly indicated the successful synthesis of GOC. The percentage of gelatin amino groups reacted with OA was up to 50% as determined using the 2,4,6-trinitrobenzene sulfonic acid (TNBS) method. Subsequently, gelatin-oleic nanoparticles (GONs) were prepared using a desolvation method with glutaraldehyde or genipin used as a crosslinker for comparison. Irinotecan hydrochloride (IRT) was used as a model drug to load into GONs using incubation or an in-process adding method for comparison. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) data showed that the sizes of GONs and IRT-loaded GONs (IRT-GONs) were below 250 nm. The zeta potentials of the GONs and irinotecan-loaded IRT-GONs were below -20 mV, which was found to be stable in suspension against the aggregation process. The incubation method was more suitable for drug loading because it did not affect the process of GON formation and thus did not increase their size much compared to the change in size with the in-process adding method. The lipophilic property of the oleic moiety in the GOC increased the affinity between GOC molecules, thus reducing the amount of crosslinking agents needed to stabilize GONs compared to gelatin nanoparticles (GNs). As novel approaches for the synthesis of protein-fatty acid complexes, chemical reaction has been suggested for the synthesis of GOC. The above results show that GOC synthesized via new method is a promising biomaterial based upon preparation of nanoparticles., (Copyright © 2014 Elsevier B.V. All rights reserved.)

To investigate the performance of a solid-state self-nanoemulsifying system with no precipitation in gastric and intestinal fluid, itraconazole (ITZ) was selected as a model drug because of its practically insoluble nature in intestinal fluid. A self-nanoemulsifying ITZ solid dispersion (SNESD) system was prepared as follows: (1) establishment of self-nanoemulsifying composition via the hot melting method, (2) solidification with fumed silicon dioxide (Aerosil 300) via adsorption to prepare SNESD and (3) preparation of a directly compressible tablet containing SNESD. This SNESD was easily formulated in the form of a dissolving tablet and provided a favourable nanoemulsifying microenvironment with no precipitation in the testing media. The SNESD and SNESD-loaded tablet displayed highly enhanced dissolution via nanomisation (266.8 nm and 258.3 nm at 60 min and 120 min, respectively), whereas the drug alone or a reference ITZ Sporanox® capsule displayed very low dissolution and precipitated immediately in intestinal fluid. Drug precipitation in intestinal fluid may affect the in vivo performance of poorly soluble weakly basic drugs and was estimated according to the crystal growth theory. The superdisintegrant and surfactant in the formulation of the tablet were very crucial to the dissolution of the SNESD-loaded tablet. The drug contents and dissolution rates of the SNESD-loaded tablets were also stable during storage in terms of dissolution and drug content. The SNESD-loaded tablet displayed significantly increased oral bioavailability in healthy human volunteers compared with the reference Sporanox® capsule. The current solid-state SNESD-loaded tablet could provide an alternative to liquid-based emulsifying preparations for various poorly water-soluble drugs without precipitation in testing media., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The aim of this study was to investigate the pharmacokinetics and biodistribution in Sprague-Dawley rats, anti-tumor activity and acute toxicity in different tumor-bearing mice of novel biocompatible nanoparticles. Paclitaxel (PTX) was selected as a model drug and loaded on different tumor types and at various doses. The nanoparticles were prepared using a newly synthesized gelatin-oleic acid conjugate via self-assembly in an aqueous solution. The nanoparticles were further functionalized using folic acid (FA) as a targeting ligand for cancer. The in vivo effects of the nanoparticles were compared with the commercially available Taxol (a solution form of PTX) as a reference dosage form. The in vivo studies confirmed that nanoparticles showed improved therapeutic effects on tumors and significantly reduced the toxic effects associated with Taxol, even at the 50% lethal dose (LD50). The in vivo pharmacokinetic parameters and biodistribution of the nanoparticles containing PTX also indicated slower clearance, longer blood circulation and higher tumor selectivity. Furthermore, the functionalized nanoparticles with FA were more effective than the non-functionalized nanoparticles. Thus, the suitable properties of gelatin-oleic nanoparticles (GON) as a drug carrier and the effective targeting ligand could synergistically maximize the in vivo anti-tumor efficacy resulting in delayed tumor volume growth and hence, providing versatile strategies in cancer therapy and drug delivery.

Recently, we synthesized novel amphiphilic gelatin-oleic acid (GO) conjugate to prepare self-assembled nanoparticles for drug delivery. The aim of this study was to investigate pharmaceutical potentialities of self-assembled GO nanoparticles for solubility enhancement and modified release of poorly water-soluble drugs. Three poorly water-soluble model drugs with different pH-dependent solubility (valsartan and aceclofenac, insoluble at pH 1.2; telmisartan, insoluble at pH 6.8) were chosen to investigate the potential contributions of self-assembled GO nanoparticles to solubility enhancement and controlled release. The particle size of the drug-loaded nanoparticles was 200-250 nm. Zeta potential was calculated, and instrumental analysis such as powder X-ray diffraction (PXRD) and Fourier transform infrared (FT-IR) spectroscopy were used to investigate the physicochemical properties of the drug-loaded nanoparticles. Compared to the drug alone, the drug-loaded nanoparticles showed enhanced solubility. Furthermore, the release profiles of the model drugs were modified in a controlled manner. The current self-assembled GO nanoparticles can provide a versatile potential in drug delivery and tumor targeting., (Copyright © 2013 Elsevier B.V. All rights reserved.)

For the past few decades biomedical engineering has imprinted its significant impact on the map of science through its wide applications on many other fields. An important example obviously proving this fact is the versatile application of magnetic nanoparticles in theranostics. Due to preferable properties such as biocompatibility, non-toxicity compared to other metal derivations, iron oxide-based magnetic nanoparticles was chosen to be addressed in this review. Aim of this review is to give the readers a whole working window of these magnetic nanoparticles in the current context of science. Thus, preparation of magnetic iron oxide nanoparticles with the so-far techniques, methods of characterizing the nanoparticles as well as their most recent biomedical applications will be stated.

Alginate microparticles were prepared using an air atomization method and varying formulation and processing conditions. Thereafter, the size and surface morphology of alginate microparticles were characterized. The trapping efficiencies of the ketoconazole, acetaminophen, vitamin C, and Bifidobacteria bifidum as model core materials were then determined. The air atomization process produced free-flowing and small-size microparticles after the freeze-drying process. The size distribution and surface morphology varied depending on the concentration of wall-forming materials and processing conditions. Generally, the geometric mean size increased as the concentration of alginate and poly-1-lysine and the delivery rate increased, but the air pressure decreased. Most of all, the ratio of delivery rate of alginate solution and air pressure could affect the size and surface morphology of alginate microparticles. However, the geometric mean size of alginate poly-1-lysine microparticles reproducibly ranged from about 80 to 130 μm. The microparticles were irregularly spherical or elliptical. The trapping efficiencies of ketoconazole, acetaminophen, vitamin C, and bifidobacteria were determined to be 71.5%, 60.1%, 1.6%, and 31%, respectively, when alginate concentration (1.5%), poly-1-lysine concentration (0.02%), air pressure (0.75 bar), delivery rate (8 ml/min), and spraying distance (45 cm) were applied. The current microencapsulation process using the air atomization method provides an alternative to entrapping small molecules and macromolecules without using harmful organic solvents. In addition, the small-size and free-flowing alginate microparticles containing active substances can be used as an intermediate in pharmaceutical applications. [ABSTRACT FROM AUTHOR]

Cellular properties and microenvironments, as well as the characteristics of nanoparticles (NPs), affect the cellular uptake and cytotoxic effects of drug-loaded NPs. Since there is fluid flow in the human blood system, fluid flow also affects the drug delivery efficiency of NPs. This study aimed to evaluate the cellular behaviors of drug-loaded soft NPs on A549 cancer cells under different levels of shear stress (0.5, 5, and 50 dynes/cm2) in the biomimetic microfluidic system. The soft self-assembled NPs were formed by the gelatin–oleic conjugate (GOC). The poorly water-soluble coumarin-6 or paclitaxel (PTX) were used as model markers for encapsulation within self-assembled NPs (C-GONs or PTX-GONs, respectively). The cellular uptake of C-GONs was found to be improved with shear-stress dependence. The inhibitory concentration (IC50) of PTX-GONs at 0.5, 5, and 50 dynes/cm2 was 0.106 µg/mL, 0.108 µg/mL, and 0.091 µg/mL, respectively, as compared to 0.138 µg/mL in a static condition. The cell killing efficiency of PTX-GONs was increased in the highest shear stress of 50 dynes/cm2 in the static condition, and other levels of shear stress in dynamic conditions. [ABSTRACT FROM AUTHOR]

A new conceptual nanoparticle consisting of a silica-coated iron oxide magnetic core and a fattigation-based biocompatible shell with oleic acid and hydrophilic protein (gelatin). The prepared particle can be a useful theranostics platform material for diagnostic imaging and as a drug delivery system. Oleic acid and gelatin were conjugated on the silica-coated magnetic nanoparticle surface to provide three primary functionalities: 1) enhancing biocompatibility and solubility in aqueous solution and providing the ability to incorporate hydrophobic chemical drugs into the shell for delivery, 2) improving treatment-response magnetic monitoring as a diagnostic agent with low nanotoxicity, and 3) increasing anticancer efficacy owing to the controlled release of the incorporated drug in cells and in an animal model. We prepared magnetic-silica nanoparticles with super-paramagnetic properties, which are utilized as a T 2 -weighted magnetic resonance imaging agent. After formation of an oleic acid-gelatin shell, the prepared materials exhibited high loading capacity for a hydrophobic anticancer drug (paclitaxel). Our particle platform system exhibited higher therapeutic efficacy and lower toxicological effects in vitro and in an in vivo cancer model than a clinically available chemo-drug (Taxol®). Our findings strongly suggest that this nanoparticle system can serve as a platform for cancer therapy by the incorporation of chemical drugs. [ABSTRACT FROM AUTHOR]

Abstract: Superparamagnetic iron oxide (SPIO) nanoparticles have been intensively investigated as MRI probes due to the noninvasive detection of in vivo pathological changes. In the study, a nanosized system for SPIO delivery to a tumor was prepared to overcome the common challenges of SPIO nanoparticles such as insufficient uptake of SPIO by specific cells due to instability, short half-life by macrophage, and low efficiency of internalization. SPIO with ca. 6nm sizes as a MRI probe and PLA–PEG (5K–2K) as a biocompatible stable system were prepared. The hydrophobic modified SPIO were loaded into the core of micelles and showed a stable dispersion with 140–170nm particle sizes. The SPIO loading micelles showed higher relaxivity coefficients and increases of T 2 relaxation in vivo MR imaging. This SPIO delivery system with high stability and sensitivity can be a promising imaging formulation as MRI T 2 probes for tumor detection. [Copyright &y& Elsevier]