N‐(2‐hydroxypropyl)methacrylamide‐based polymer conjugates with pH‐controlled activation of doxorubicin. I. New synthesis,physicochemical characterization and preliminary biological evaluation

New method of synthesis of water‐soluble polymer‐drug conjugates, exhibiting remarkable anticancer activity in mice models, has been developed. In the conjugates, an anticancer drug doxorubicin (DOX) is attached to a polymer carrier based on N‐(2‐hydroxypropyl)methacrylamide (HPMA) copolymer via a hydrolytically labile hydrazone bond. New methacrylamide‐type comonomers, containing either hydrazide group or hydrazon of DOX, were used for copolymerization with HPMA. In contrast to the synthetic procedure described earlier the new method is simpler, cheaper, and results in a better‐defined conjugate structure. The conjugates are fairly stable in buffer at pH 7.4 (model of blood stream) but release DOX under mild acid conditions modeling the tumor microenvironment. The conjugates showed significant in vivo antitumor activity in treatment of T‐cell lymphoma EL‐4 bearing mice with up to 100% long‐term survivors. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Preparation and efficacy of tumor vasculature‐targeted doxorubicin cationic liposomes coated by N‐trimethyl chitosan

Cationic liposomes (CLs) can accumulate in tumor vascular endothelial cells (VECs) to show high selective targeting ability. Therefore, chemotherapeutic agent‐loaded CLs are considered as new therapeutic vehicles to enhance the treatment efficacy. This study investigated the effect of N‐trimethyl chitosan (TMC), one of derivatives of chitosan with positive charge determined by its degree of quaternization (DQ), on preparing doxorubicin (DOX)‐loaded CLs. TMCs with various DQ, i.e., 20% (TMC20), 40% (TMC40), and 60% (TMC60) were synthesized and characterized by ¹HNMR. DOX‐loaded liposomes (DOXL) were prepared by ammonium sulfate gradients followed by TMC‐coating to obtain TMC‐coated DOXL with various positive surface charges. The morphology, size, ζ‐potential and drug release in vitro of TMC‐coated DOXL were studied compared with those of DOXL. Human umbilical vein endothelial cells (HUVECs) as cell model, the vascular targeting ability of TMC‐coated DOXL was evaluated in vitro. A solid tumor, formed by implantationmurine hepatoma cells (H₂₂) into mice, as tumor model, the tumor inhibition rate and tumor histological sections stained by HE of TMC‐coated DOXL group were researched compared with those of free DOX and DOXL group. It was found that with the increase of TMC's DQ, the positive surface charge of TMC‐coated DOXL was enhanced accordingly, which had little effect on DOX release in vitro while led to the significant increase of DOX uptake by HUVECs in vitro and the treatment effect on solid tumor in vivo. Especially, TMC‐coated DOXL showed better targeting ability to the nuclei compared with free DOX and DOXL, which could further enhance the efficacy of DOX in vivo. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Cytotoxicity of cationic liposomes coated by N‐trimethyl chitosan and their in vivo tumor angiogenesis targeting containing doxorubicin

Doxorubicin (DOX)‐loaded cationic liposomes (DOXL) coated by N‐trimethyl chitosan (TMCs) has been previously shown to enhance DOX uptake by human umbilical vein endothelial cells (HUVECs) in vitro and the tumor inhibition on solid tumor in vivo, and the effects were both enhanced with the degree of quaternization (DQ) increase of TMCs. The aim of the present work is to study the cytotoxicity of the blank cationic liposomes (CLs) coated by TMCs with various DQ on L‐929 mouse fibroblasts, by MTT assay, using the relative proliferation rate as the indicator, and the toxicity extent was classified according to the evaluation criteria of United States Pharmacopoeia. Furthermore, the in vivo tumor angiogenesis targeting of DOXL coated by TMC60 was studied. It was found that with the increase of TMCs concentration and DQ, cytotoxicity was increased accordingly. However, the cell proliferation rates of TMCs‐coated CLs with TMCs concentrations of 0.02% and 0.05%(w/w) were all above 80%, even the concentration of TMC20 was increased to 0.2%(w/w), the cell proliferation rate was still above 80%, showing noncytotoxicity. The mouse H₂₂ tumor model was established by transplanted tumor experiment. In vivo fluorescence in tumor tissue was investigated through the tail vein injection of fluorescein isothiocyanate conjugated dextran at the 7th day after the administration of different DOX preparations. Compared with DOX solution and uncoated DOXL, the mice given TMC60‐coated DOXL showed tumor angiogenesis with good shape, uniform arrangement, and small vascular branches, and the vascular density was decreased, suggesting promising tumor angiogenesis targeting of TMC60‐coated DOXL. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

pH‐sensitive hydroxyethyl starch–doxorubicin conjugates as antitumor prodrugs with enhanced anticancer efficacy

Doxorubicin (DOX) is a widely used chemotherapeutic drug for the treatment of several types of cancers, which has limitation in clinical applications because of severe heart toxicity. Herein, to reduce the fast clearance from the blood system and the severe systemic toxicity caused by the nonspecific protein adsorption, a pH‐sensitive drug delivery system with higher drug conjugated content was prepared by conjugating DOX onto hydroxyethyl starch (HES) with a pH‐sensitive hydrazone bond. In normal physiological environment, the release of DOX conjugated onto HES was slight which could be neglected without any side effect. However, in an acidic environment mimicking the tumor microenvironment, this pH‐sensitive hydrazone linkage provided a controlled and sustained release of DOX over a period of more than 3 days. The conjugates had good biocompatibility, long circulation, and lower cytotoxicity, which could efficiently be transferred into HeLa and HepG2 cells and release the conjugated drug. Based on these promising properties, these HES–DOX conjugates outline the significant potential for future biomedical application in the controlled release of antitumor drugs. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42778.     

Intracellular pH‐sensitive dextran‐based micelles as efficient drug delivery platforms

As drug delivery systems, stimuli‐responsive polymer micelles hold great potential in cancer chemotherapeutics to improve therapeutic efficiency and eliminate organism adverse effects. Here, pH‐sensitive polymeric micelles based on dextran‐g‐benzimidazole were designed and used for intracellular anticancer drug delivery. The anticancer drug doxorubicin (DOX) was effectively loaded into the micelles via hydrophobic interactions. In vitro release studies demonstrated that the release of loaded DOX was greater and faster under acid conditions such as in carcinomatous areas (pH < 6.8) than in physiological conditions (pH 7.4). MTT assays and flow cytometric analyses showed that DOX‐loaded micelles had higher cellular proliferation inhibition towards HeLa and HepG2 cells than pH‐insensitive controls. These pH‐sensitive micelles with significant efficiency for intracellular drug release will be beneficial to the future of in vivo biomedical applications. © 2014 Society of Chemical Industry     

Antitumor efficacy of doxorubicin encapsulated within PEGylated poly(amidoamine) dendrimers

We report here a general approach to using poly(amidoamine) (PAMAM) dendrimers modified with polyethylene glycol (PEG) as a platform to encapsulate an anticancer drug doxorubicin (DOX) for in vitro cancer therapy applications. In this approach, PEGylated PAMAM dendrimers were synthesized by conjugating monomethoxypolyethylene glycol with carboxylic acid end group (mPEG‐COOH) onto the surface of generation 5 amine‐terminated PAMAM dendrimer (G5.NH₂), followed by acetylation of the remaining dendrimer terminal amines. By varying the molar ratios of mPEG‐COOH/G5.NH₂, G5.NHAc‐mPEG_n (n = 5, 10, 20, and 40, respectively) with different PEGylation degrees were obtained. We show that the PEGylated dendrimers are able to encapsulate DOX with approximately similar loading capacity regardless of the PEGylation degree. The formed dendrimer/DOX complexes are water soluble and stable. In vitro release studies show that DOX complexed with the PEGylated dendrimers can be released in a sustained manner. Further cell viability assay in conjunction with cell morphology observation demonstrates that the G5.NHAc‐mPEG_n/DOX complexes display effective antitumor activity, and the DOX molecules encapsulated within complexes can be internalized into the cell nucleus, similar to the free DOX drug. Findings from this study suggest that PEGylated dendrimers may be used as a general drug carrier to encapsulate various hydrophobic drugs for different therapeutic applications. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40358.     

Influence of polyethylene glycol molecular weight on the anticancer drug delivery of pH-sensitive polymeric micelle

Polyethylene glycol (PEG) and pH-sensitive polymers have been widely utilized in anticancer drug delivery systems due to their characteristics of prolonging circulation time and tumor-responsive drug release. However, the effect of PEG molecular weight on the delivery of anticancer drug-encapsulating pH-sensitive polymer micelles has been poorly studied. Therefore, a simple method was used to prepare pH-sensitive doxorubicin (DOX)-loaded micelles (DOX/POD) based on polyethylene glycol-2-(octadecyloxy)-1, 3-dioxan-5-amine (POD) polymers, and the influence of PEG molecular weights (1 K, 2 K, and 5 K) on in vitro drug release and antitumor effect was further studied. Interestingly, as the molecular weight increased, the release amount of DOX was augmented. While the cytotoxicity and cellular uptake were increased, the molecular weight was decreased. It is reasonable to speculate that the high molecular weight of PEG may promote the dissolution rate of DOX, and their micelles with uncompact structure are being prone to disassembly in an acid environment. However, the low molecular weight of PEG may contribute to the formation of compact POD micelles, which make it easier to be uptaken by tumor cells resulting in the enhanced antitumor effect. Taken together, the results indicate that pH-sensitive POD micelles with low molecular weight can achieve the efficient delivery of drugs, and PEG molecular weight in pH-sensitive nanocarriers may influence the antitumor effect. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47854.     

PEGylated polylysine derived copolymers with reduction‐responsive side chains for anticancer drug delivery

Reduction‐responsive drug delivery systems have recently gained intense attention in intracellular delivery of anticancer drugs. In this study, we developed a PEGylated polypeptide, poly(ethylene glycol)‐block‐poly(?‐propargyloxycarbonyl‐l ‐lysine) (PEG₁₁₃‐b‐PPAL), as a novel clickable substrate for conjugation of reduction‐responsive side chains for antineoplastic drug delivery. PEG₁₁₃‐b‐PPAL was synthesized through ring‐opening polymerization of alkyne‐containing N‐carboxyanhydride monomers. A designed disulfide‐containing side chain was introduced onto the PEGylated polypeptide by click reaction. The obtained copolymer PEG₁₁₃‐b‐P(Lys‐DSA) formed micelles by self‐assembly, which exhibited reduction‐responsive behavior under the stimulus of 10 mmol L^–1 glutathione (GSH) in water. A small molecule intermediate, compound 2 , was used as a model to investigate the thiol reduction mechanism of PEG₁₁₃‐b‐P(Lys‐DSA) copolymers. The anticancer drug doxorubicin (DOX) was then loaded into the micelles with a drug loading content of 6.73 wt% and a loading efficiency of 40.3%. Both the blank and the drug‐loaded micelles (DOX‐loaded polylysine derived polymeric micelles (LMs/DOX)) adopted a spherical morphology, with average diameters of 48.0 ± 13.1 and 63.8 ± 20.0 nm, respectively. The in vitro drug release results indicated that DOX could be released faster from the micelles by the trigger of GSH in phosphate buffered saline. Confocal laser scanning microscopy and flow cytometer analysis further proved the intracellular delivery of DOX by LMs/DOX and their GSH‐sensitive release behavior. A 3‐(4,5‐dimethyl‐thiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay showed that the polymers exhibited negligible cytotoxicity towards normal L929 cells or cancer MCF‐7 cells with a treated concentration up to 1.0 mg mL^–1. In conclusion, our synthesized biocompatible and biodegradable PEGylated polypeptides hold great promise for intracellular antineoplastic drug delivery. © 2019 Society of Chemical Industry     

Molecular‐Target‐Based Anticancer Photosensitizer: Synthesis and in vitro Photodynamic Activity of Erlotinib–Zinc(II) Phthalocyanine Conjugates

Targeted photodynamic therapy is a new promising therapeutic strategy to overcome growing problems in contemporary medicine, such as drug toxicity and drug resistance. A series of erlotinib–zinc(II) phthalocyanine conjugates were designed and synthesized. Compared with unsubstituted zinc(II) phthalocyanine, these conjugates can successfully target EGFR‐overexpressing cancer cells owing to the presence of the small molecular‐target‐based anticancer agent erlotinib. All conjugates were found to be essentially non‐cytotoxic in the absence of light (up to 50 μM ), but upon illumination, they show significantly high photo‐cytotoxicity toward HepG2 cells, with IC₅₀ values as low as 9.61–91.77 nM under a rather low light dose (λ=670 nm, 1.5 J cm^?2). Structure–activity relationships for these conjugates were assessed by determining their photophysical/photochemical properties, cellular uptake, and in vitro photodynamic activities. The results show that these conjugates are highly promising antitumor agents for molecular‐target‐based photodynamic therapy.     

Liver‐targeting doxorubicin‐conjugated polymeric prodrug with pH‐triggered drug release profile

The aim of the research presented was to develop a potential liver‐targeting prolonged‐circulation polymeric prodrug of doxorubicin (Dox) with a pH‐triggered drug release profile. In particular, linear dendritic block copolymers composed of polyamidoamine dendrimer (PAMAM) and poly(ethylene glycol) (PEG; number‐average molecular weight of 2000 g mol^?1) with or without galactose (Gal) were synthesized. Dox was coupled to the copolymers via an acid‐labile hydrazone linker. These prodrugs, designated Gal‐PEG‐b‐PAMAM‐Dox_n and mPEG‐b‐PAMAM‐Dox_m, showed accelerated Dox release as the pH decreased from 8.0 to 5.6. Cytotoxicity of the prodrugs was lower than that of free Dox due to the gradual drug release nature. Compared to mPEG‐b‐PAMAM‐Dox_m, Gal‐PEG‐b‐PAMAM‐Dox_n showed rather high cytotoxicity against Bel‐7402, suggestive of its galactose receptor‐mediated enhanced tumor uptake. This galactose receptor‐mediated liver‐targeted profile was further confirmed by the prolonged retention time in hepatoma tissue monitored using magnetic resonance imaging. Gal‐PEG‐b‐PAMAM‐Dox_n showed better in vivo antitumor efficacy than free Dox, suggesting its great potential as a polymeric antitumor prodrug. Copyright © 2010 Society of Chemical Industry     

Effect of degree of substitution and molecular weight of carboxymethyl chitosan nanoparticles on doxorubicin delivery

The aim of this study was to evaluate the potential of carboxymethyl chitosan (CM‐chitosan) nanoparticles as carriers for the anticancer drug, doxorubicin (DOX). Different kinds of CM‐chitosan with various molecular weight (MW) and degree of substitution (DS) were employed to prepare nanoparticles through ionical gelification with calcium ions. Factors affecting nanoparticles formation in relation to MW and DS of CM‐chitosan were discussed. By the way of dynamic light scattering (DLS), TEM, and atomic force microscopy (AFM), nanoparticles were shown to be around 200–300 nm and in a narrow distribution. FTIR revealed strong electrostatic interactions between carboxyl groups of CM‐chitosan and calcium ions. DOX delivery was affected by the molecular structure of CM‐chitosan. Increasing MWs of CM‐chitosan from 4.50 to 38.9 kDa, DOX entrapment efficiency was enhanced from 10 to 40% and higher DS slightly improved the load of DOX. In vitro release studies showed an initial burst followed by an extended slow release. The DOX release rate was hindered by CM‐chitosan with high MW and DS. These preliminary studies showed the feasibility of CM‐chitosan nanoparticles to entrap DOX and the potential to deliver it as controlled release nanoparticles. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 4689–4696, 2006     

Structure–property relationship of pH‐sensitive (PCL)2(PDEA‐b‐PPEGMA)2 micelles: Experiment and DPD simulation

The experiment and dissipative particle dynamics simulation were carried out on four polymers with different block ratios for the investigation of the structure–property relationship of (poly(ε‐caprolactone)₂‐[poly(2‐(diethylamino)ethyl methacrylate)‐b‐poly(poly(ethylene glycol) methyl ether methacrylate)]₂ [(PCL)₂(PDEA‐b‐PPEGMA)₂] micelles. The miktoarm star polymers assembled into spherical micelles composed of PCL core, pH‐sensitive PDEA mesosphere and poly (ethylene glycol) methyl ether methacrylate (PPEGMA) shell. When decreasing pH from 7.4 to 5.0, the hydrodynamic diameter and transmittance of (PCL)₂(PDEA‐b‐PPEGMA)₂ micelles increased along with globule‐uneven‐extended conformational transitions, owing to the protonation of tertiary amine groups of DEA at lower pH conditions. Doxorubicin (DOX) was mainly loaded in the pH‐sensitive layer, and more DOX were loaded in the core when increasing drug concentrations. The in vitro DOX release from the micelles was significantly accelerated by decreasing pH from 7.4 to 5.0. The results demonstrated that the pH‐sensitive micelles could be used as an efficient carrier for hydrophobic anticancer drugs, achieving controlled and sustained drug release. © 2014 American Institute of Chemical Engineers AIChE J, 60: 3634–3646, 2014     

PEGylated hollow pH‐responsive polymeric nanocapsules for controlled drug delivery

Novel pH‐responsive PEGylated hollow nanocapsules (HNCaps) were fabricated through a combination of distillation–precipitation copolymerization and surface thiol–ene ‘click’ grafting reaction. For this purpose, SiO₂ nanoparticles were synthesized using the Stöber approach, and then modified using 3‐(trimethoxysilyl)propyl methacrylate (MPS). Afterward, a mixture of triethyleneglycol dimethacrylate (as crosslinker), acrylic acid (AA; as pH‐responsive monomer) and MPS‐modified SiO₂ nanoparticles (as sacrificial template) was copolymerized using the distillation–precipitation approach to afford SiO₂@PAA core–shell nanoparticles. The SiO₂ core was etched from SiO₂@PAA using HF solution, and the obtained PAA HNCaps were grafted with a thiol‐end‐capped poly(ethylene glycol) (PEG) through a thiol–ene ‘click’ reaction to produce PAA‐g‐PEG HNCaps. The fabricated HNCaps were loaded with doxorubicin hydrochloride (DOX) as a model anticancer drug, and their drug loading and encapsulation efficiencies as well as pH‐dependent drug release behavior were investigated. The anticancer activity of the drug‐loaded HNCaps was extensively evaluated using MTT assay against human breast cancer cells (MCF7). The cytotoxicity assay results as well as superior physicochemical and biological features of the fabricated HNCaps mean that the developed DOX‐loaded HNCaps have excellent potential for cancer chemotherapy. © 2020 Society of Chemical Industry     

Effects of the process parameters on the initial burst release of poly(lactide‐co‐glycolide) microspheres containing bovine serum albumin by the double‐emulsion solvent evaporation/extraction method

The effects of fabrication parameters on the morphology, drug loading, and initial burst release of poly(lactide‐co‐glycolide) microspheres loaded with bovine serum albumin were investigated to establish an optimal process and system for the in vivo delivery of therapeutic proteins. Through the addition of salts or sugars to induce an osmotic pressure in the external water phase, large microspheres were seen to have their morphology, drug loading, and initial burst release significantly affected. However, the effect was not observed for compact microspheres less than 10 μm in diameter. The presence of poly(vinyl alcohol), Pluronic F127, and Tween 80 in the internal water phase had detrimental effects on the drug loading because of the depressed stability of the primary emulsion and competitive interactions of surface‐active substances with the polymer. However, the simultaneous addition of salts to the external water phase resulted in enhanced drug loading and decreased initial burst. The polymer concentration and volume of the internal water phase were important factors influencing the characteristics of the microspheres. These parameters were optimized for achieving the maximal drug loading and a low initial burst. The solvent extraction method yielded microspheres with a higher drug loading and a lower initial burst in comparison with the solvent evaporation method. Different ranges of protein encapsulation efficiencies were obtained with blends of poly(lactide‐co‐glycolide) and poly(ethylene glycol), depending on the molecular weight and content of poly(ethylene glycol). © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Self‐organized nanogels from pullulan‐g‐poly(L‐lactide) synthesized by one‐pot method: Physicochemical characterization and in vitro doxorubicin release

Water‐insoluble pullulan‐g‐poly(L ‐lactide) (PUPL) was successfully synthesized via a one‐pot method in the presence of triethylamine in dimethyl sulfoxide, in an effort to design a novel anticancer agent carrier. Three samples (designated as PUPL 1, 2, and 3) were obtained, which differed in the moles of lactides grafted to the pullulan. The degrees of grafted lactide per 1 glucose unit in pullulan were 0.68, 0.60, and 0.45 for PUPL 1, 2, and 3, respectively. These copolymers were dissolved in several organic solvents, including dimethyl sulfoxide, acetone, and ethanol, but were insoluble in water. The self‐organized nanogels were then prepared from the polymers via dialysis. To study the organizing behavior of the polymers, their critical association concentrations were measured. Their values were 5.0, 15.9, and 52.9 mg/L for PUPL 1, 2, and 3, respectively. The results showed that lactide in the polymers could function as a hydrophobic moiety for the formation of self‐organized nanogels. To estimate the potential of PUPL 1 as an anticancer drug carrier, we used doxorubicin (DOX) as a model drug. The DOX loading efficiencies of PUPL 1 were more than 52%, which differed with differing initial DOX concentrations. High loading resulted in slower DOX release as the result of increases in hydrophobic interaction. In conclusion, PUPL nanogels may prove useful as anticancer drug carriers because of their low critical association concentrations and the controlled DOX release rate © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

F3-functionalized nanoscale metal–organic frameworks for tumor-targeting combined chemotherapy and chemodynamic therapy

Nanoscale metal–organic frameworks (nMOFs) have attracted much attention as emerging porous materials as drug delivery carriers. Appropriate surface modification of them can greatly improve stability and introduce biocompatibility and cancer targeting functionality into drug delivery systems. Herein, we prepared nano-sized MIL-101(Fe)-N₃ and loaded anticancer drug doxorubicin (DOX) into it. The synthetic polymer layer Alkyne-PLA-PEG was then attached to the F3 peptide (labeled as Alkyne-PLA-PEG-F3), and the surface of DOX/MIL-101(Fe)-N₃ was covalently modified with it to obtain DOX/MIL-101-PLA-PEG-F3. Nano-sized MIL-101(Fe)-N₃ has high drug loading capacity and the modification of MIL-101(Fe)-N₃ by polymer Alkyne-PLA-PEG not only improved the dispersion, but also avoided the sudden release of the drugs and increased the biocompatibility of nanocarriers. The F3 peptide introduced into the nanocarriers also enabled it to specifically target tumor tissues and achieved active targeted drug delivery. As a nucleolin-mediated endocytosis drug delivery system, DOX/MIL-101-PLA-PEG-F3 can not only deliver anticancer drugs to tumors accurately, but also participate in Fenton-like reaction to generate hydroxyl radicals (•OH) for chemodynamic therapy (CDT), thus enabling combination therapy. It holds great promise as drug candidates to reduce systemic toxicity and improve the efficacy of cancer treatment.     

Self‐assembled nanoparticles from folate‐decorated maleilated pullulan–doxorubicin conjugate for improved drug delivery to cancer cells

The goal of this study was to develop doxorubicin conjugate nanoparticles with increased antitumor effects, reduced side effects and the ability to overcome multidrug resistance (MDR). In this regard, folate‐decorated maleilated pullulan–doxorubicin conjugate nanoparticles were developed as carriers for co‐delivery of pyrrolidinedithiocarbamate and doxorubicin (FA‐MP‐DOX/PDTC + DOX NPs). The resultant nanoparticles showed spherical geometry, with an average diameter of 152 nm. The two drugs were released from the nanoparticles in a slow, pH‐dependent sustained release. To test the efficacy of these nanoparticles, in vitro tests including cell viability and folate receptor‐mediated endocytosis were conducted against both A2780 cells and A2780/DOX^R cells. Compared to free DOX, the FA‐MP‐DOX/PDTC + DOX NPs showed effective but less potent cytotoxicity against A2780 cells. For A2780/DOX^R cells, they showed enhanced cellular uptake, increased targeting capacity and cytotoxicity. These results suggest that co‐delivery of PDTC and DOX may further overcome MDR by transporting an increased amount of DOX within cells in addition to the folate receptor‐mediated endocytosis process. © 2012 Society of Chemical Industry     

Polyurethane/doxorubicin nanoparticles based on electrostatic interactions as pH‐sensitive drug delivery carriers

In order to obtain a pH‐sensitive delivery carrier for doxorubicin (DOX), DOX‐loaded polyurethane (PU·DOX) nanoparticles were readily prepared in water by electrostatic interactions between amphiphilic polyurethane with carboxyl pendent groups (PU‐COOH) and doxorubicin hydrochloride (DOX·HCl). The structures of the products obtained were characterized by Fourier transform infrared spectroscopy, ¹H NMR spectroscopy, gel permeation chromatography, UV–visible spectroscopy, dynamic light scattering and transmission electron microscopy. The average hydrodynamic size of the PU·DOX nanoparticles was around 182 nm with negative surface charge (?1.1 mV) and a spherical or rodlike shape. PU·DOX nanoparticles had a higher drug‐loading content of 14.1 wt%. The in vitro drug release properties of PU·DOX nanoparticles were investigated at pH 4.0, 5.0 and 7.4, respectively. PU·DOX nanoparticles exhibited a good pH‐sensitive drug release property, but there was almost no release of DOX from PU·DOX nanoparticles at pH 7.4. The in vitro cellular uptake assay and the Cell Counting Kit‐8 assay demonstrated that PU·DOX nanoparticles had a higher level of cellular internalization and higher inhibitory effects on the proliferation of human breast cancer (MCF‐7) cells than pure DOX. The enhancement of the inhibition effects resulted from increasing apoptosis‐inducing effects on MCF‐7 cells, which was related to the enhancement of Bax expression and the reduction of Bcl‐2 expression confirmed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay, real‐time polymerase chain reaction (PCR) assay and western blot assay. © 2018 Society of Chemical Industry     

Functionalized bacterial cellulose nanowhiskers as long‐lasting drug nanocarrier for antibiotics and anticancer drugs

A nano drug carrier based on sustainable and biocompatible nanocellulose was developed for use in prolonged drug releases. The grafting of β‐cyclodextrin (βCD) on bacterial cellulose nanowhiskers (BCNC) using citric acid (CA) as a green linker was performed. This led to the formation of functionalized BCNC‐grafted‐βCD (BCNC‐g‐βCD). Broad‐spectrum antibiotic Ciprofloxacin (CIP) and anticancer drugs Doxorubicin (DOX) and Paclitaxel (PTX) were used as model drugs. These model drugs were conjugated to BCNC‐g‐βCD to form the drug‐nanocarrier systems (BCNC‐g‐βCD‐drug). The change in the nanowhiskers’ surface chemistry, morphology, and crystallinity was characterized by FTIR, solid‐state ¹³C NMR, scanning electron microscopy (SEM), atomic force microscopy (AFM), and x‐ray diffraction (XRD). The functionalized nanowhiskers showed a significant increase in the drug payloads, which ranged from 495 ±4–810 ±7 μg/mg, along with a radical improvement in the drug release profiles. For all of the developed drug‐conjugated nanocarriers, the initial burst releases were reduced effectively. The observed drug releases showed a sustained and controlled manner, with cumulative releases of 75–90 % over 5–5.5 days. Nevertheless, an improved drug release performance was observed in the acidic pH of 6.4 that mimicked extracellular tumor cells. In vitro drug release data were fitted zero‐order kinetic model with drug release constants (K₀) of 0.68, 0.74, and 0.79 μg drug/h (at pH 6.4 and 37 °C) for BCNC‐g‐βCD‐CIP, BCNC‐g‐βCD‐DOX, and BCNC‐g‐βCD‐PTX nanosystems, respectively. The observed higher payloads along with the slow releases of drugs from the developed nanocarrier suggests its promising potential for reducing the frequent daily dosing and minimizing systemic toxicity of loaded drugs.