pH-responsive Drug Delivery Vehicles Research Articles

Fabrication and Investigation of Oxidized-β-Cyclodextrin Nanoparticle as a Novel Class pH Responsive Drug Delivery Vehicle

Fabrication and Investigation of Oxidized-β-Cyclodextrin Nanoparticle as a Novel Class pH Responsive Drug Delivery Vehicle

Development of a Cu/ZnO@ZIF-8 nanocomposite as a pH-responsive drug delivery vehicle for the sustained release of doxorubicin in human lung cancer cell lines

Nowadays the targeted drug release from a stable and non-toxic drug delivery vehicle is an onerous task. In this work, we developed a ZIF-8 based nanocomposite by the incorporation of copper doped zinc oxide nanoparticles onto the ZIF-8 frameworks. The formation of the composite was confirmed with the help of various spectral analyses such as FTIR, UV–visible, PXRD, XPS, TEM, SEM-EDS, TG/DTG, BET, and photoluminescent spectroscopy. The feasibility of the material as a drug delivery vehicle was analyzed by loading doxorubicin (DOX) and monitoring its release in human lung cancer cell line A549 under different pH conditions such as 1.2, 5.5, and 7.4. The release kinetics is in good agreement with the Higuchi model with a regression coefficient of 0.9999. The composite possesses a better drug loading capacity of 43.2 % and follows a sustained release kinetics at pH 5.5. The biocompatibility of the material is also noticed by monitoring the in vitro cytotoxicity and anticancer activity through MTT assay. The composite material shows a cytotoxicity of 71.99 % against human lung cancer cell line A549 and cell viability of 37 % towards the normal fibroblast cell line L929 at 100 μg/mL. The anticancer activity of the composite loaded with DOX was compared with the pure DOX. The results showed that the composite loaded with DOX shows better anticancer activity than that of pure DOX with an IC50 of 69.89 μg/mL, lower than that of pure DOX (85.52 μg/mL). The combined effect such as better drug loading, sustained and pH-responsive release and potential anticancer activity leads to the conclusion that the ZIF-8 based nanocomposite can be used as a better therapeutic agent against human lung cancer cell line A549.

Design and characterizations of pH-responsive drug delivery vehicles using molecular docking

ABSTRACT Performing wet bench experiments to search for lead molecules for drug delivery is a long and tedious process where computational tools have played a crucial role. Molecular docking studies have been carried out for selecting the nanocarrier, and the results of the computational studies have been validated using the model protein Ova albumin and anticancer drug 5-Fluorouracil (5-FU) with mesoporous silica (MSNPs) and chitosan nanoparticles (CSNPs) as the nanocarriers. Formulated nanocarriers were tested for in-vitro release, which showed a sustained release of the drugs. In-vitro studies on the lung cancer cell line A459 revealed excellent biocompatibility and non-toxic nature of the designed drug delivery system. This chitosan nanoparticle-based drug delivery system could have the potential for chemotherapeutic treatment of cancer.

A facile strategy to construct fluorescent pH-sensitive drug delivery vehicle

Aliphatic polyesters have led to significant advancements in drug delivery systems spanning decades owing to their biocompatibility and biodegradability. A series of pH-sensitive aliphatic polyesters were synthesized by facile enzymatic polymerization, which could be post-modified by click chemistry to form multifunctional graft copolymers. Typically, the hydrophilic methoxy polyethylene glycol (mPEG) and fluorescent coumarin were grafted onto the polyester backbone to constitute a multifunctional amphipathic graft copolymer, serving as a trackable pH-responsive drug delivery vehicle. This amphipathic graft copolymer could encapsulate hydrophobic doxorubicin (DOX) via self-assembly in aqueous solutions and performed superior controlled drug release. And the in vitro cellular uptake and cytotoxicity results showed the feasibility of this system for drug delivery application. Collectively, this copolymer offers a potential route of constructing controlled drug delivery system.

Aromatic Nitrogen Mustard-Based Autofluorescent Amphiphilic Brush Copolymer as pH-Responsive Drug Delivery Vehicle.

Delivery of clinically approved nonfluorescent drugs is facing challenges because it is difficult to monitor the intracellular drug delivery without incorporating any integrated fluorescence moiety into the drug carrier. The present investigation reports the synthesis of a pH-responsive autofluorescent polymeric nanoscaffold for the administration of nonfluorescent aromatic nitrogen mustard chlorambucil (CBL) drug into the cancer cells. Copolymerization of poly(ethylene glycol) (PEG) appended styrene and CBL conjugated N-substituted maleimide monomers enables the formation of well-defined luminescent alternating copolymer. These amphiphilic brush copolymers self-organized in aqueous medium into 25-68 nm nanoparticles, where the CBL drug is enclosed into the core of the self-assembled nanoparticles. In vitro studies revealed ∼70% drug was retained under physiological conditions at pH 7.4 and 37 °C. At endolysosomal pH 5.0, 90% of the CBL was released by the pH-induced cleavage of the aliphatic ester linkages connecting CBL to the maleimide unit. Although the nascent nanoparticle (without drug conjugation) is nontoxic, the drug conjugated nanoparticle showed higher toxicity and superior cell killing capability in cervical cancer (HeLa) cells rather than in normal cells. Interestingly, the copolymer without any conventional chromophore exhibited photoluminescence under UV light irradiation due to the presence of "through-space" π-π interaction between the C═O group of maleimide unit and the adjacent benzene ring of the styrenic monomer. This property helped us intracellular tracking of CBL conjugated autofluorescent nanocarriers through fluorescence microscope imaging. Finally, the 4-(4-nitrobenzyl)pyridine (NBP) colorimetric assay was executed to examine the ability of CBL-based polymeric nanomaterials toward alkylation of DNA.

Facile synthesis of Prussian blue nanoparticles as pH-responsive drug carriers for combined photothermal-chemo treatment of cancer

Multifunctional PEGylated PB-DOX NPs with a lipid-PEG shell were developed as a gram-scale manner and used as novel pH-responsive drug delivery vehicles for combined photothermal-chemo treatment of cancer cells with high efficacy.

Fe3O4@carbon@zeolitic imidazolate framework-8 nanoparticles as multifunctional pH-responsive drug delivery vehicles for tumor therapy in vivo.

Controlled drug release is a promising approach for cancer therapy due to its merits of reduced systemic toxicity and enhanced antitumor efficacy. Here, multifunctional Fe3O4@carbon@zeolitic imidazolate framework-8 (FCZ) hybrid nanoparticles (NPs) were successfully constructed. Owing to the porosity and acid-sensitivity of zeolitic imidazolate framework-8 (ZIF-8), FCZ NPs not only displayed an improved drug loading capacity compared to most of the polymeric nanocarriers, but also exhibited excellent pH-triggered release of doxorubicin (DOX) in vitro. Moreover, carbon dots (CDs) embedded in the porous carbon shell and superparamagnetic iron oxide nanocrystals could simultaneously function as intracellular fluorescence imaging and T2*-weighted magnetic resonance imaging (MRI) contrast agents, respectively. The results obtained from the MTT assay demonstrated good biocompatibility of FCZ NPs. DOX release experiments showed pH regulation-dominated drug release kinetics: a weak acidic pH in tumor areas could trigger sustained drug release, suggesting that FCZ NPs are ideal drug delivery systems. Moreover, the remarkable inhibition of tumor growth without side effects was confirmed in vivo. These results provide convincing evidence establishing the multifunctional FCZ NPs as promising candidates for tumor therapy.

PEGylated dendritic diaminocyclohexyl-platinum (II) conjugates as pH-responsive drug delivery vehicles with enhanced tumor accumulation and antitumor efficacy

Environmentally responsive peptide dendrimers loaded with drugs are suitable candidates for cancer therapy. In this study, we report the preparation and characterization of mPEGylated peptide dendrimer-linked diaminocyclohexyl platinum (II) (dendrimer-DACHPt) conjugates as pH-responsive drug delivery vehicles for tumor suppression in mice. The DACHPt has a molecular structure, is and activity closely related to oxaliplatin and was linked to dendrimer via N,O-chelate coordination. The products were pH-responsive and released drug significantly faster in acidic environments (pH 5.0) than pH 7.4. Consequently, the conjugates suppressed tumor growth better than clinical oxaliplatin® without inducing toxicity in an SKOV-3 human ovarian cancer xenograft. Through the systemic delivery of conjugates, 25-fold higher tumor platinum uptake at 36 h post-injection was seen observed due to the enhanced permeability and retention (EPR) effect thereby remarkably enhancing the therapeutic indexes of this small-molecule drug. Thus, the mPEGylated peptide dendrimer-linked DACH-platinum conjugates are novel potential drug delivery systems with implications in future ovarian cancer therapy.

PUA/PSS multilayer coated CaCO3 microparticles as smart drug delivery vehicles

Hybrid CaCO3 microparticles coated by sodium poly(styrene sulfonate) (PSS) and aliphatic poly(urethane-amine) (PUA) were developed as thermal-/pH-responsive drug delivery vehicles via LbL self-assembly technique. The DOX release from the CaCO3 microparticles was higher than 60% within 36h, whereas the value of PUA/PSS-coated microparticles was only 20%. The results demonstrated that the PUA/PSS multilayer coating could reduce the drug release rate and significantly assuage the initial burst release of DOX. In addition, the drug release of the hybrid microparticles was found to be thermal-/pH-dual responsive. More interestingly, more than 90% of DOX was released in 36h at pH2.1 and 55°C owing to the combined action of the dissolution of the CaCO3 core and the shrinkage of aliphatic PUA.

Poly methacrylic acid modified CDHA nanocomposites as potential pH responsive drug delivery vehicles

The objective of this study was to prepare pH sensitive polymethacrylic acid-calcium deficient hydroxyapatite (CDHA) nanocomposites. The CDHA nanoparticles were prepared by coprecipitation method. The modification of CDHA by methacrylic acid (MA) was achieved by AIBN initiated free radical polymerization with sodium bisulphite as catalyst followed by emulsion technique. These nanocomposites with a half life of 8h consisted of high aspect ratio, needle like particles and exhibited an increase in swelling behaviour with pH. The in vivo potential of the nanocomposites was evaluated in vitro by the results of cell aggregation, protein adsorption, MTT assay and haemolytic activity. The invitro loading and release studies using albumin as a model drug indicate that the nanocomposites gave better loading when compared to the CDHA nanoparticles and altered the drug release rates. The nanocomposites also exhibited good uptake on C6 glioma cells as studied by fluorescence microscopy. The results obtained suggest that these nanocomposites have great potential for oral controlled protein delivery and can be extended further for intracellular drug delivery applications.

Nanoparticle Formation from Hybrid, Multiblock Copolymers of Poly(Acrylic Acid) and VPGVG Peptide.

Elastin-mimetic hybrid copolymers with an alternating molecular architecture were synthesized via the step growth polymerization of azide-functionalized, telechelic poly(tert-butyl acrylate) (PtBA) and an alkyne-terminated, valine and glycine-rich peptide with a sequence of (VPGVG)2 (VG2). The resultant hybrid copolymer, [PtBA-VG2]n, contains up to six constituent building blocks and has a polydispersity index (PDI) of ~1.9. Trifluoroacetic acid (TFA) treatment of [PtBA-VG2]n gave rise to an alternating copolymer of poly(acrylic acid) (PAA) and VG2 ([PAA-VG2]n). The modular design permits facile adjustment of the copolymer composition by varying the molecular weight of PAA (22 and 63 repeat units). Characterization by dynamic light scattering indicated that the multiblock copolymers formed discrete nanoparticles at room temperature in aqueous solution at pH 3.8, with an average diameter of 250-270 nm and a particle size distribution of 0.34 for multiblock copolymers containing PAA22 and 0.17 for those containing PAA63. Upon increasing the pH to 7.4, both types of particles were able to swell without being disintegrated, reaching an average diameter of 285-300 nm for [PAA22-VG2]n and 330-350 nm for [PAA63-VG2]n, respectively. The nanoparticles were not dissociated upon the addition of urea, further confirming their unusual stability. The nanoparticles were capable of sequestering a hydrophobic fluorescent dye (pyrene), and the critical aggregation concentration (CAC) was determined to be 1.09 × 10-2 or 1.05 × 10-2 mg/mL for [PAA22-VG2]n and [PAA63-VG2]n, respectively. We suggest that the multiblock copolymers form through collective H-bonding and hydrophobic interactions between the PAA and VG2 peptide units, and that the unusual stability of the multiblock nanoparticles is conferred by the multiblock architecture. These hybrid multiblock copolymers are potentially useful as pH-responsive drug delivery vehicles, with the possibility of drug loading through concerted H-bonds and hydrophobic interactions.