pH-responsive Drug Carriers Research Articles

Synthesis of amphiphilic copolymers containing zwitterionic sulfobetaine as pH and redox responsive drug carriers

Amphiphilic poly(ɛ-caprolactone)-SS-poly(N,N-diethylaminoethyl methacrylate)-r-poly(N-(3-sulfopropyl)-N-methacrylate-N,N-diethylammonium-betaine) (PCL-SS-PDEASB) was designed and synthesized successfully. pH and redox dually responsive micelles were prepared based on the obtained copolymers, with zwitterionic sulfobetaines as hydrophilic shell, DEA as pH sensitive content and disulfide as redox responsive linkage. The micelle diameters were all less than 200nm and the micelle diameter distributions were narrow. These micelles could be triggered by pH and redox condition. The drug release from the drug-loaded micelles displayed fastest under simultaneously acidic and reductive conditions. Results of in vitro cell toxicity evaluation showed that introduction of sulfobetaines could greatly decrease the toxicity of poly(ɛ-caprolactone)-SS-poly(N,N-diethylaminoethyl methacrylate) (PCL-SS-PDEA) micelles. DOX-loaded PCL-SS-PDEASB micelles showed higher efficiency to kill HeLa cells than DOX-loaded PCL-PDEASB micelles. Half inhibitory concentration (IC50) of DOX-loaded PCL-SS-PDEASB micelles decreased with the content of sulfobetaines increasing and was even closer to that of DOX·HCl. Thus, the pH and redox dually responsive biodegradable micelles generated by PCL-SS-PDEASB may be potential smart drug carriers for tumor targeted delivery.

Dual-responsive polymer–drug nanoparticles for drug delivery

A well-defined, dual temperature- and pH-responsive drug carrier was synthesized through the radical copolymerization of methacrylic acid, N-isopropylacrylamide, and an N-(methacryloyl)glycylglycine 4-nitrophenyl ester. When the anticancer agent gemcitabine or antibiotic sulfamethoxazole was conjugated with a polymer and heated beyond its low critical solution temperature (40°C), a dual temperature- and pH-induced phase transition was observed. This temperature was considered ideal for activating drug aggregation under hyperthermic and acidic conditions. The structure and properties of polymer drugs were investigated using nuclear magnetic resonance, Fourier transform infrared spectrometry, ultraviolet–visible absorption, transmission electron microscopy, and gel permeation chromatography. At a critical micelle concentration of 1mg/mL, both polymer drugs formed micellar structures with diameters ranging from 50nm to 150nm, based on TEM image. These micelles exhibited higher pharmacological efficacy than the free drug alone did, and the cytotoxicity at the target site was substantially enhanced compared with that of the polymer–drug conjugate formed under normal physiological conditions.

Abstract 4477: pH-responsive PEG-HPAH micelles for drug delivery and their potential in cancer therapy

Abstract pH-responsive hyperbranched polymers have attracted much attention due to their unique properties for tumor-targeted drug delivery. In this study, we describe a pH-responsive drug carrier, poly (ethylene glycol) (PEG)-hyperbranched polyacylhydrazone (HPAH), which can form nanoscale micelles to be used as anti-cancer drug carriers with pH-controlled drug release. The molecular structure of PEG-HPAH was confirmed by nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FTIR). The drug-loaded micelles with a diameter of approximately 190 nm, were prepared using a dialysis method against PBS with a pH of 8.0. The drug-loaded micelles showed the desired pH-dependent drug release properties. The drug release levels were low at neutral and alkaline pH, but increased significantly with a decrease in the pH of the medium. Intracellular uptake results indicated that the PEG-HPAH-drug micelles could efficiently deliver chemotherapeutic drugs into the cells. In addition, it was found that the subcellular localization of the drug-loaded micelles was different from that of free drugs, in which the drug-loaded micelles were mainly in the cytoplasm. The docetaxel (DTX)-loaded PEG-HPAH micelles presented a high cytotoxic activity against tumor cells in vitro. When combined with the administration of glucose, the PEG-HPAH-DTX micelles exhibited a superior anti-tumor efficacy and a lower systemic toxicity in vivo. The biodistribution profile showed increased accumulated drug levels in tumor tissue and plasma in micelles treated group. The results indicate that the nanoscale PEG-HPAH-DTX micelles may serve as a novel selective tumor-targeting drug delivery system. Citation Format: Qin Xu, Jingshuang Yu, Bangshang Zhu. pH-responsive PEG-HPAH micelles for drug delivery and their potential in cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4477. doi:10.1158/1538-7445.AM2014-4477

Hydrophobically modified spherical MCM-41 as nanovalve system for controlled drug delivery

Spherical MCM-41 nanovalve having hydrophobically modified pore channels was synthesized via surfactant assisted sol–gel methodology and post modification process. The spherical MCM-41 has been tailored as a smart pH responsive drug carrier system by the insertion of N-3-(trimethoxysilyl)propyl aniline (TMSPA) at the pore opening before extracting the surfactant and further with phenyltrimethoxysilane (PTMS) to impart hydrophobicity on the inner surfaces of the pore channels. The surfactant extracted MCM-41 exhibits excellent textural properties such as very high specific surface area (1307 m2g−1), pore diameter (24 Å) and pore volume (0.65 cm3g−1). The transmission electron microscope (TEM) and scanning electron microscope (SEM) images of mesosphere reflect the highly uniform and mono-dispersed spherical morphology having a particle size of 500nm. 5-Fluorouracil (5-Fu) and famotidine have been loaded into the hydrophobically modified channels followed with β-cyclodextrin (β-CD) as the gatekeeper to make the material as a pH responsive drug delivery system. The drug delivery has been carried out under in vitro condition at pH 4 and the amount of drug released from the nanovalve system was monitored by UV–Vis spectroscopy under regular intervals. The hydrophobically modified nanovalve was found to have delayed drug release of both 5-Fu and famotidine in comparison to the drug delivery from the nanovalve having unmodified pore channels synthesized from spherical MCM-41 under similar experimental conditions. The significance of functionalization as well as capping has been verified by the comparison of drug delivery behaviors among hydrophobically modified, unmodified, β-CD capped and uncapped nanocontainers.

Hydrazone-bearing PMMA-functionalized magnetic nanocubes as pH-responsive drug carriers for remotely targeted cancer therapy in vitro and in vivo.

To develop vehicles for efficient chemotherapeutic cancer therapy, we report a remotely triggered drug delivery system based on magnetic nanocubes. The synthesized magnetic nanocubes with average edge length of around 30 nm acted as cores, whereas poly(methyl methacrylate) (PMMA) was employed as an intermediate coating layer. Hydrazide was then tailored onto PMMA both for doxorubicin (DOX) loading and pH responsive drug delivery via the breakage of hydrazine bonds. The successful fabrication of the pH responsive drug carrier was confirmed by transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and magnetic hysteresis loops, respectively. The carrier was stable at neutral environment and doxorubicin released at pH of 5.0. Cell viability assay and confocal laser scanning microscopy observations demonstrated that the loaded DOX could be efficiently released after cellular endocytosis and induced cancer cells apoptosis thereby. More importantly, the carrier could be guided to the tumor tissue site with an external magnetic field and led to efficient tumor inhibition with low side effects, which were reflected by magnetic resonance imaging (MRI), change of tumor size, TUNEL staining, and H&E staining assays, respectively. All results suggest that hydrazide-tailoring PMMA-coated magnetic nanocube would be a promising pH-responsive drug carrier for remotely targeted cancer therapy in vitro and in vivo.

The potential of pH-responsive PEG-hyperbranched polyacylhydrazone micelles for cancer therapy

pH-responsive hyperbranched polymers have attracted much attention due to their unique properties for tumor-targeted drug delivery. In this study, we describe a pH-responsive drug carrier, poly (ethylene glycol) (PEG)-hyperbranched polyacylhydrazone (HPAH), which can form nanoscale micelles to be used as anti cancer drug carriers with pH-controlled drug release. The molecular structure of PEG-HPAH was confirmed by nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FTIR). The drug-loaded micelles with a diameter of approximately 190 nm, were prepared using a dialysis method against PBS with a pH of 8.0. The drug-loaded micelles showed the desired pH-dependent drug release properties. The drug release levels were low at neutral and alkaline pH, but increased significantly with a decrease in the pH of the medium. Intracellular uptake results indicated that the PEG-HPAH-drug micelles could efficiently deliver chemotherapeutic drugs into the cells. In addition, it was found that the subcellular localization of the drug-loaded micelles was different from that of free drugs, in which the drug-loaded micelles were mainly in the cytoplasm. The docetaxel (DTX)-loaded PEG-HPAH micelles presented a high cytotoxic activity against tumor cells in vitro. When combined with the administration of glucose, the PEG-HPAH-DTX micelles exhibited a superior anti-tumor efficacy and a lower systemic toxicity in vivo. The biodistribution profile showed increased accumulated drug levels in tumor tissue and plasma in micelles treated group. The results indicate that the nanoscale PEG-HPAH-DTX micelles may serve as a selective tumor-targeting drug delivery system.

Synthesis of uniform core–shell gelatin–alginate microparticles as intestine‐released oral delivery drug carrier

A core-shell gelatin-alginate composite used for intestine-released oral delivery drug carrier was synthesized through microfluidic technique. At the fixed continuous phase flow rate, the size of the core-shell gelatin-alginate microparticles increases with the dispersed phase flow rate, and monodispersity can be retained (the variation coefficient for the diameter distribution can be kept less than 10%). The fabricated microparticles could remain intact in gastric juice for at least 3 h, indicating that the gelatin core could be well protected by alginate shell in acid environment. However, the alginate shell of the microparticles would swell or collapse in alkali environment in half an hour, assuring the controlled drug release in intestinal juice. The fabricated uniform core-shell gelatin-alginate microparticles were potential as pH-responsive drug carriers.

Cyclodextrin Derivatives Conjugated with Aromatic Moieties as pH-responsive Drug Carriers for Anthracycline

The modification of cyclodextrins (CDs) with side chains containing aromatic groups was found to lead to an increase of the stability of the complex with the anticancer drug doxorubicin (Dox). The formation constants evaluated by voltammetry were several orders of magnitude larger than that of the unmodified β-CD ligand. For the CDs with aromatic moieties connected by linkers containing a triazole group, the formation constants of the complexes at pH 5.5 and 7.4 were very different. At lower pH, binding was much weaker as a result of protonation of the triazole moiety in the linker. The drug was then released from the complex. Molecular modeling of the Dox-β-CD system revealed different possible interactions between Dox and β-CD. The observed pH dependence of the complex formation constant can be exploited for drug delivery to the targeted cells. The toxicities of the synthesized complexes and each of the complex components were tested by the MTT assay on two cell lines, the human lung carcinoma and human cervical cancer cell lines.

Poly(acrylic acid) modified lanthanide-doped GdVO4hollow spheres for up-conversion cell imaging, MRI and pH-dependent drug release

In this study, multifunctional poly(acrylic acid) modified lanthanide-doped GdVO(4) nanocomposites [PAA@GdVO(4): Ln(3+) (Ln = Yb/Er, Yb/Ho, Yb/Tm)] were constructed by filling PAA hydrogel into GdVO(4) hollow spheres via photoinduced polymerization. The up-conversion (UC) emission colors (green, red and blue) can be tuned by changing the codopant compositions in the matrices. The composites have potential applications as bio-probes for cell imaging. Meanwhile, the hybrid spheres can act as T(1) contrast agents for magnetic resonance imaging (MRI) owing to the existence of Gd(3+) ions on the surface of composites. Due to the nature of PAA, DOX-loaded PAA@GdVO(4):Yb(3+)/Er(3+) system exhibits pH-dependent drug releasing kinetics. A lower pH offers a faster drug release rate. Such character makes the loaded DOX easily released at cancer cells. The cell uptake process of drug-loaded composites was observed by using confocal laser scanning microscopy (CLSM). The results indicate the potential application of the multifunctional composites as theragnostics (effective bimodal imaging probes and pH-responsive drug carriers).

Facile PEGylation of Boltorn® H40 for pH-responsive drug carriers

A pH-responsive drug delivery system was developed through facile PEGylation of commercial aliphatic dendritic polyester Boltorn® H40 (H40) by forming the acetal linkages. Benefiting from its amphiphilic structure, the star copolymer (H40-star-MPEG) with a hydrophobic H40 core and many hydrophilic poly(ethylene glycol) (MPEG) arms was able to self-assemble into stable micelles in aqueous solution. Moreover, the size of self-assembled micelles could be easily tailored by only changing the grafting ratio of MPEG chains. The degradable behavior of H40-star-MPEG was measured by NMR technique under neutral and acidic deuterium aqueous medium. The experimental results showed that a fast hydrolysis of H40-star-MPEG occurred at a low pH solution, resulting from the cleavage of acetal linkages. The low cytotoxicity of H40-star-MPEG micelles was confirmed by cell evaluation. As a model anticancer drug, the hydrophobic drug doxorubicin (DOX) was encapsulated into the self-assembled H40-star-MPEG micelles. In an acidic environment, the drug release of DOX-loaded micelles was accelerated greatly. The DOX-loaded micelles could be internalized by the cancer cells efficiently, resulting in the effective inhibition to cancer cell proliferation. All of these results suggest that facile PEGylation of H40 with acetal linkages provides a promising pH-responsive drug carrier for cancer therapy.

Mechanisms of Drug Resistance Reversal in Dox-Resistant MCF-7 Cells by pH-Responsive Amphiphilic Polyphosphazene Containing Diisopropylamino Side Groups

pH-responsive drug carriers derived from polymers containing weak base groups have been shown to improve the antitumor effect of chemotherapeutics. The common interpretation is that a "proton sponge effect" caused by pH-responsive polymers facilitates endosomal membrane destruction and accelerates cytoplasmic drug release in tumor cells. However, the mechanisms by which pH-responsive weak base polymers disrupt membranes have not been expatiated clearly. Herein, we synthesized a series of pH-responsive amphiphilic polyphosphazenes containing diisopropylamino (DPA) side groups with various contents and investigated the effect of DPA content on the actions of polymers with cell membranes. In a certain pH range, the polymers with elevated DPA content showed enhanced membrane disruptive activity. Electrical interactions between the protonated DPA groups of polymers and the cell lipid bilayer are critical for pH-dependent membrane disruption, which can be competitively prevented by serum proteins. On the other hand, the hydrophobic unprotonated DPA moieties can insert into lipophilic regions of cell membrane. These synergic actions caused the alteration of biomembrane permeability consequently. More interestingly, it was also found that DPA-rich polymers exhibit higher P-glycoprotein (P-gp) inhibition activity as compared with the polymer containing only low levels of DPA by efficiently blocking the internal epitope of P-gp. These findings strongly provide rational support for pH-responsive amphiphilic polyphosphazenes containing DPA side groups to be quite promising drug carriers for intracellular drug delivery applications, especially the treatment of P-gp overexpressing, drug-resistant tumors.

PH-Responsive Copolymer Assemblies for Controlled Release of Doxorubicin

pH-Responsive drug carriers have the potential to provide selective drug release at therapeutic targets including tumors and in acidic intracellular vesicles such as endosomes and lysosomes. We have developed a new approach to the design of acid-sensitive micelles by incorporating hydrophobic acetal groups on the core block of a micelle-forming block copolymer. Hydrolysis of the acetals at mildly acidic pH is designed to reveal polar groups on the core-forming block, thus changing its solubility and disrupting the micelle, triggering drug release. The anticancer drug doxorubicin (DOX) was encapsulated in these pH-sensitive micelles, and the acetal hydrolysis rates and DOX release rates were determined in the pH range of 4.0 to 7.4 and were compared to those of control systems. The micelle disruption was investigated by dynamic light scattering. The in vitro toxicities of the empty and DOX-loaded micelles were determined, and the intracellular fate of the encapsulated DOX was compared to free DOX using fluorescence confocal microscopy.