pH-responsive Release Of Doxorubicin Research Articles

Hollow-structured covalent organic framework decorated with FA-PEG: A biocompatible nanocarrier for targeted and pH-responsive release of doxorubicin

Hollow nanostructures hold great promise for drug delivery applications due to their considerable capabilities for efficient drug encapsulation alongside distinct physicochemical attributes. Herein, an imine-linked hollow nanosphere covalent organic framework (COF) with high surface area and well-structured porosity was developed serving as a versatile drug delivery system (DDS) to achieve targeted and effective delivery of doxorubicin (DOX) as a chemotherapeutic agent. The production of COF hollow nanoparticles included the use of a heterogeneous nucleation and growth method, followed by the subsequent encapsulation of DOX. Following this, the nanoparticles underwent functionalization with folate-poly (ethylene glycol)-amine (FA-PEG) using a bonding defect strategy. An in vitro cytotoxicity assay and flow cytometry study against FR-negative HEK293 and FR-positive MCF7 cells were performed, revealing that FA-PEG-functionalized HCOF exhibited a unique targeting effect on cancer cells, surpassing the impact of DOX@HCOF on FR-positive MCF7 cancer cells. Additionally, the hollow architecture of the COF is engineered to undergo disintegration selectively under conditions of cancer cell pH, facilitating the comprehensive release of DOX. The pH-responsive and tumor-targeted attributes of the DOX@HCOF-PEG-FA open new avenues for incorporating structural engineered HCOFs as a promising drug carrier capable of regulating drug release and augmenting therapeutic efficacy.

Targeted Hyperbranched Nanoparticles for Delivery of Doxorubicin in Breast Cancer Brain Metastasis.

Breast cancer brain metastases (BM) are associated with a dismal prognosis and very limited treatment options. Standard chemotherapy is challenging in BM patients because the high dosage required for an effective outcome causes unacceptable systemic toxicities, a consequence of poor brain penetration, and a short physiological half-life. Nanomedicines have the potential to circumvent off-target toxicities and factors limiting the efficacy of conventional chemotherapy. The HER3 receptor is commonly expressed in breast cancer BM. Here, we investigate the use of hyperbranched polymers (HBP) functionalized with a HER3 bispecific-antibody fragment for cancer cell-specific targeting and pH-responsive release of doxorubicin (DOX) to selectively deliver and treat BM. We demonstrated that DOX-release from the HBP carrier was controlled, gradual, and greater in endosomal acidic conditions (pH 5.5) relative to physiologic pH (pH 7.4). We showed that the HER3-targeted HBP with DOX payload was HER3-specific and induced cytotoxicity in BT474 breast cancer cells (IC50: 17.6 μg/mL). Therapeutic testing in a BM mouse model showed that HER3-targeted HBP with DOX payload impacted tumor proliferation, reduced tumor size, and prolonged overall survival. HER3-targeted HBP level detected in ex vivo brain samples was 14-fold more than untargeted-HBP. The HBP treatments were well tolerated, with less cardiac and oocyte toxicity compared to free DOX. Taken together, our HER3-targeted HBP nanomedicine has the potential to deliver chemotherapy to BM while reducing chemotherapy-associated toxicities.

Enhanced Immunogenic Cell Death and Antigen Presentation via Engineered Bifidobacterium bifidum to Boost Chemo-immunotherapy.

The immunogenic cell death (ICD) of tumor cells has aroused great interest in the field of immunotherapy, mainly due to the production of plentiful tumor-associated antigens (TAAs) and damage-associated molecule patterns. However, doxorubicin (DOX)-induced tumor-specific T-cell-mediated immune response is usually very weak because of antigen presentation deficiency and the immunosuppressive tumor microenvironment (ITME). Herein, the probiotic Bifidobacterium bifidum (Bi) was covalently modified with DOX-loaded CaP/SiO2 nanoparticles (DNPs@Bi) for tumor therapy. On one hand, the pH-responsive release of DOX could induce chemotherapy and ICD in the ITME. On the other hand, tumor-targeting Bi is able to significantly enhance the presentation of TAAs from B16F10 cells to DCs via Cx43-dependent gap junctions. Due to the combination of enhanced ICD and TAAs presentation, the maturation of DCs and the infiltration of cytotoxic T lymphocytes in the ITME were stimulated. As a result, in vivo antitumor experiments demonstrated that DNPs@Bi prolonged the survival rate and significantly inhibited the tumor progression and metastasis. This strategy of bacterial-driven hypoxia-targeting delivery systems offers a promising approach to tumor chemo-immunotherapy.

Unimolecular Micelles from Randomly Grafted Arborescent Copolymers with Different Core Branching Densities: Encapsulation of Doxorubicin and In Vitro Release Study

A series of amphiphilic arborescent copolymers of generations G1 and G2 with an arborescent poly(γ-benzyl L-glutamate) (PBG) core and poly(ethylene oxide) (PEO) chain segments in the shell, PBG-g-PEO, were synthesized and evaluated as drug delivery nanocarriers. The PBG building blocks were generated by ring-opening polymerization of γ-benzyl L-glutamic acid N-carboxyanhydride (Glu-NCA) initiated with n-hexylamine. Partial or full deprotection of the benzyl ester groups followed by coupling with PBG chains yielded a comb-branched (arborescent polymer generation zero or G0) PBG structure. Additional cycles of deprotection and grafting provided G1 and G2 arborescent polypeptides. Side chains of poly(ethylene oxide) were then randomly grafted onto the arborescent PBG substrates to produce amphiphilic arborescent copolymers. Control over the branching density of G0PBG was investigated by varying the length and the deprotection level of the linear PBG substrates used in their synthesis. Three G0PBG cores with different branching densities, varying from a compact and dense to a loose and more porous structure, were thus synthesized. These amphiphilic copolymers behaved similar to unimolecular micelles in aqueous solutions, with a unimodal number- and volume-weighted size distributions in dynamic light scattering measurements. It was demonstrated that these biocompatible copolymers can encapsulate hydrophobic drugs such as doxorubicin (DOX) within their hydrophobic core with drug loading efficiencies of 42-65%. Sustained and pH-responsive DOX release was observed from the unimolecular micelles, which suggests that they could be useful as drug nanocarriers for cancer therapy.

CD13-Mediated Pegylated Carboxymethyl Chitosan-Capped Mesoporous Silica Nanoparticles for Enhancing the Therapeutic Efficacy of Hepatocellular Carcinoma.

Liver cancer, especially hepatocellular carcinoma, is an important cause of cancer-related death, and its incidence is increasing worldwide. Nano drug delivery systems have shown great promise in the treatment of cancers. In order to improve their therapeutic efficacy, it is very important to realize the high accumulation and effective release of drugs at the tumor site. In this manuscript, using doxorubicin (DOX) as a model drug, CD13-targeted mesoporous silica nanoparticles coated with NGR-peptide-modified pegylated carboxymethyl chitosan were constructed (DOX/MSN-CPN). DOX/MSN-CPN comprises a spherical shape with an obvious capping structure and a particle size of 125.01 ± 1.52 nm. With a decrease in pH, DOX/MSN-CPN showed responsive desorption from DOX/MSN-CPN and pH-responsive release of DOX was observed. Meanwhile, DOX/MSN-CPN could be efficiently absorbed through NGR-mediated internalization in vitro and could efficiently deliver DOX to tumor tissues with long accumulation times in vivo, suggesting good active targeting properties. Moreover, significant tumor inhibition has been observed in antitumor studies in vivo. This study provides a strategy of utilizing DOX/MSN-CPN as a nano-platform for drug delivery, which has superb therapeutic efficacy and safety for the treatment of hepatocellular carcinoma both in vivo and in vitro.

Preparation of a pH-responsive chitosan-montmorillonite-nitrogen-doped carbon quantum dots nanocarrier for attenuating doxorubicin limitations in cancer therapy.

Despite its widespread usage as a chemotherapy drug in cancer treatment, doxorubicin (DOX) has limitations such as short in vivo circulation time, low solubility, and poor permeability. In this regard, a pH‐responsive chitosan (CS)‐ montmorillonite (MMT)‐ nitrogen‐doped carbon quantum dots (NCQDs) nanocomposite was first developed, loaded with DOX, and then incorporated into a double emulsion to further develop the sustained release. The incorporated NCQDs into the CS‐MMT hydrogel exhibited enhanced loading and entrapment efficiencies. The presence of NCQDs nanoparticles in the CS‐MMT hydrogel also resulted in an extended pH‐responsive release of DOX over a period of 96 h compared to that of CS‐MMT‐DOX nanocarriers at pH 5.4. Based on the Korsmeyer‐Peppas model, there was a controlled DOX release at pH 5.4, while no diffusion was observed at pH 7.4, indicating fewer side effects. MTT assay showed that the cytotoxicity of DOX‐loaded CS‐MMT‐NCQDs hydrogel nanocomposite was significantly higher than those of free DOX (p < 0.001) and CS‐MMT‐NCQDs (p < 0.001) on MCF‐7 cells. Flow cytometry results demonstrated that a higher apoptosis induction achieved after incorporating NCQDs nanoparticles into CS‐MMT‐DOX nanocarrier. These findings suggest that the DOX‐loaded nanocomposite is a promising candidate for the targeted treatment of cancer cells.

Construction of Folate-Conjugated and pH-Responsive Cell Membrane Mimetic Mixed Micelles for Desirable DOX Release and Enhanced Tumor-Cellular Target.

Smart multifunctional polymeric micelles are in urgent demand for future cancer diagnosis and therapy. In this paper, doxorubicin (DOX)-loaded folic acid (FA)-targeting and pH-responsive cell membrane mimetic mixed micelles of P(DMAEMA-co-MaPCL) (PCD) and FA-P(MPC-co-MaPCL) (PMCF) (mass ratio 5/5) were prepared by a dialysis method. The micelle size, morphology, X-ray powder diffraction (XRD), pH responsiveness, in vitro DOX release, cytotoxicity, and cellular uptake were studied in detail. The results indicated that DOX could be efficiently loaded into mixed micelles (PDMCF micelles), and the DOX-loaded mixed micelles (DOX@PDMCF micelles) exhibited a size of 150 nm and pH-responsive DOX release in an extended period. Furthermore, the DOX@PDMCF micelles could efficiently suppress the proliferation of tumor cells, HeLa and MCF-7 cells. Our data suggest that the DOX@PDMCF micelles have the potential to be applied in tumor therapy, especially for treating various folate receptor overexpressed tumors.

PEGylated Nanoscale Metal-Organic Frameworks for Targeted Cancer Imaging and Drug Delivery.

Nanoscale metal-organic frameworks (nMOFs) are a unique type of hybrid materials, which are broadly applicable as cargo delivery systems. However, the relatively low material stability and insufficient cancer cell interacting capacity have limited nMOFs' applications in cancer theranostics. Herein, a zirconium-based nMOF UiO-66-N3 was synthesized, and its surface was covalently functionalized with alkyne-containing polyethylene glycol (PEG) via the azide-alkyne click chemistry. After that, F3 peptide was attached for targeting of cancer cells (the material was denoted as UiO-66-PEG-F3). Doxorubicin (DOX) served as a therapeutic drug and a fluorescent label in this study, and it was transported into UiO-66-PEG conjugates with sufficient drug loading efficiency. pH-responsive release of DOX from UiO-66 conjugates was witnessed. The structural integrity of UiO-66-N3 was maintained post the surface modification process. Flow cytometry and confocal fluorescence microscopy revealed that DOX/UiO-66-PEG-F3 had stronger accumulation in MDA-MB-231 cells (nucleolin+) compared with DOX/UiO-66-PEG. In order to track the pharmacokinetic behavior (organ distribution profile) in vivo, the positron-emitting zirconium-89 (89Zr) was incorporated into UiO-66-N3. Similar PEGylation and F3 peptide conjugation resulted in the formation of 89Zr-UiO-66-PEG-F3. Serial positron emission tomography (PET) imaging demonstrated that the preferential accumulation of 89Zr-UiO-66-PEG-F3 in MDA-MB-231 tumors, and their liver clearance was faster than PEGylated UiO-66 using noncovalent methods. Thus, the PEGylated nMOFs using covalent strategies may find broad application in future cancer theranostics.

Fe3O4@PEG-coated dendrimer modified graphene oxide nanocomposite as a pH-sensitive drug carrier for targeted delivery of doxorubicin

Since dendrimer-based magnetic nanoparticles have presented remarkable potential as carriers in biomedical applications, it is worthwhile to construct a dendrimer-based drug delivery system for cancer treatment. Hence, in the present study, triazine dendrimer functionalized graphene oxide (GO-DT G2.5) was successfully fabricated by the divergent method. Then, the Fe3O4@PEG nanoparticles were attached to the surface of GO-TD G2.5 (GO-TD-Fe3O4@PEG) as a new magnetic nanocarrier for effective loading and the pH-responsive release of Doxorubicin (DOX). The structure and morphology of the synthesized GO-TD-Fe3O4@PEG were characterized by BET, XRD, DLS/ Zeta potential, UV–vis, FT‐IR, AFM, SEM, and VSM analysis. The surface morphology indicated that the average thickness of the sheets in the synthesized nanocarrier had approximately 144.21 nm. The encapsulation efficiency (EE) and drug-loading content (DLC) of this system were obtained ~92.6 and ~9.26%, respectively. The in vitro release studies of DOX from GO-TD-Fe3O4@PEG were performed at various pH values and found that the release process was noticeably controlled pHresponsive behavior. In vitro cytotoxicity studies of the as-synthesized GO-TD-Fe3O4@PEG against normal cell line (MCF-10A) and breast cancer cell line (MCF-7) confirmed that the non-toxic GO-TD-Fe3O4@PEG has excellent biocompatibility. DAPI staining and apoptosis analysis by flow-cytometry demonstrated that the apoptotic effects of GO-TD-Fe3O4@PEG-DOX have higher in comparison to free DOX. Cellular uptake also showed a high uptake percentage for GO-TD-Fe3O4@PEG-DOX than free DOX within 4 h. Therefore, the obtained results in this work suggesting that GO-TD-Fe3O4@PEG nanocomposite is a promising nanocarrier for targeted delivery and controlled release of anticancer drugs for biomedical applications.

Superparamagnetic iron oxide nanoparticles functionalized with a binary alkoxysilane array and poly(4-vinylpyridine) for magnetic targeting and pH-responsive release of doxorubicin

The reported supramolecular arrangement offers an attractive strategy for the pH-sensitive and magnetically-guided release of doxorubicin, which could allow exploring novel therapeutic schemes against cancer.

Dual pH-responsive-charge-reversal micelle platform for enhanced anticancer therapy

A novel nanodrug delivery system (NDDS) based on block copolymers of Poly(DEA)-block-Poly(PgMA) (PDPP) was developed to enhance in vitro cellular uptake and anticancer efficacy. pH-responsive doxorubicin (DOX) based small molecule prodrug (DOX-hyd-N3) and mPEG-N3 were co-conjugated onto PDPP via copper-catalyzed “Click chemistry” to give a dual pH-responsive polymeric prodrug (mPEG-g-PDPP-g-hyd-DOX), which could be self-assembled into core-shell polymeric micelles (M(DOX)) with particles size of 81 ± 1 nm in aqueous phase. Additionally, the pH-responsive charge-reversal, stability and drug release behaviour at different pHs were then evaluated. Moreover, the surface charge of M(DOX) could quickly convert from negative (−6.64 ± 3.37 mV) to positive (5.35 ± 1.33 mV) thanks to the protonation of Poly(DEA) moieties as the pH value decreased from 7.4 during blood circulation to 6.5 in extracellular of tumour tissues. Meanwhile, according to the cytotoxicity determined by CCK-8 assay, cellular uptake, flow-cytometric and apoptosis profiles of two human cancer cell lines (HeLa and SW480), we could draw the conclusion that the cellular uptake and anticancer efficacy were significantly enhanced when cells were incubated with micelles at pH 6.5 due to the charge-reversal of micelles from negative to positive. With the protonation of Poly(DEA) moieties in acidic extracellular microenvironment and the pH-responsive DOX release with hydrazone linkage in endo/lysosome pH, this dual pH-responsive-charge-reversal micelle platform might become an encouraging strategy for more effective cancer treatment.

Poly(ionic liquid)-Gated CuCo2S4 for pH-/Thermo-Triggered Drug Release and Photoacoustic Imaging.

A novel hybrid drug nanocarrier is developed with CuCo2S4 nanoparticles as the core to be encapsulated by poly(ionic liquid) (PIL), that is, poly(tetrabutylphosphonium styrenesulfonate) (P[P4,4,4,4][SS]), as the shell. Doxorubicin (DOX) is loaded onto the PIL shell via electrostatic attraction involving amine in DOX and styrenesulfonate in PIL. pH- and thermal-responsive characteristics of P[P4,4,4,4][SS] endow the multifunctional hybrid nanocarrier system DOX-CuCo2S4@PIL with sensitive dual-stimuli-triggered drug release behaviors. The CuCo2S4 core converts near-infrared (NIR) irradiation into thermal energy to trigger the shrinkage of the PIL shell, which subsequently promotes drug release, and the pH-responsive release of DOX involves pH-sensitive electrostatic interaction of the PIL shell with DOX. A favorable controlled release of 90.5% is achieved under pH/thermo dual stimuli. In vitro experiments with MCF-7 cells well demonstrated that the drug release is controlled by the acidic intracellular environment with NIR irradiation. The CuCo2S4 core also serves as a photoacoustic (PA) imaging contrast agent, as demonstrated by in vivo treatment of the MCF-7-carrying mice.

Fabrication and characterization of novel cRGD modified graphene quantum dots for chemo-photothermal combination therapy

In this work, an innovative drug delivery system based on cyclic RGD-modified (as the targeting agent) and doxorubicin-loaded graphene quantum dots (R–GQDs@DOX) was fabricated for chemo-photothermal combination therapy. These tasks include drug loading capacity, photothermal efficiency, cellular uptake and combination therapeutic effect of R–GQDs@DOX. The structure of R–GQDs@DOX was characterized by FT-IR spectrum, UV–vis spectrum and AFM. The results indicated that the doxorubicin (DOX) could be loaded onto graphene quantum dots (GQDs) via van der Waals interaction (π–π stacking) and the drug loading capacity was 96.6 % (wt). The R–GQDs@DOX not only showed obvious pH-responsive release of DOX, but also exhibited great photothermal efficacy for cancer cells. The fluorescence intensity indicated that R–GQDs@DOX was effectively taken up by SK–mel–5 and H460 cells. The combination of chemotherapy and photothermal therapy could more effectively inhibit growth of tumor cells, compared to photothermal therapy or chemotherapy alone.

Enhanced in vitro antitumor efficacy of a polyunsaturated fatty acid-conjugated pH-responsive self-assembled ion-pairing liposome-encapsulated prodrug

The development of clinical chemotherapeutics is always challenging due to the toxicity and side effects of drugs not only for tumor cells but also for normal cells. Therefore, nano-drug delivery systems and prodrug strategies have been applied to address this challenge. Herein, we report a liposome-encapsulated small-molecule prodrug nanosystem, self-assembled by doxorubicin (DOX) and mixed polyunsaturated fatty acid (MPUFA) ion-pairing (MPUFAs-DOX@Liposomes), which has a high omega-3 PUFA content. The increased lipophilicity of ion-paired MPUFAs-DOX can significantly improve the drug loading efficiency (∼97%). Electrostatic interaction, the hydrophobic effect and hydrogen bonding between the ion-pairing agents led to superior pH-responsive release of DOX from liposomes over DOX-loaded liposomes (DOX@Liposomes), with a more rapid release rate at pH 5.0 than at pH 7.4, which is beneficial for decreasing the toxicity of DOX under physiological conditions. Finally, the in vitro antitumor effects were investigated for two tumor cell types, A549 and MCF-7, and the results demonstrated that MPUFAs-DOX@Liposomes showed the highest cytotoxicity compared with free DOX and DOX@Liposomes because of the ready uptake under the effect of PUFAs. Hence, liposomes loaded with ion-paired MPUFAs-DOX is a promising formulation for combination cancer therapy.

Coordination bonding-based Fe3O4@PDA-Zn2+-doxorubicin nanoparticles for tumor chemo-photothermal therapy

Multistimuli-responsive vehicles that deliver drugs in temporal-, spatial- and dosage-controlled manners have developed as a potential platform in tumor therapy. However, how to integrate these functions in one single carrier effectively still presents a lot of challenge. Here, we developed a strategy to construct a photothermal and pH responsive platform based on Zn2+ coordination with doxorubicin (DOX) and polydopamine (PDA) on the surface of magnetic nanoparticles (Fe3O4@PDA-Zn2+-DOX NPs). In this architecture, Fe3O4@PDA nanoparticles triggered photothermal effects for tumor hyperthermia, and Zn2+ coordinated DOX was released in responding to the thermal effect to achieve chemotherapy simultaneously. Moreover, DOX release was further promoted at acidic environment due to the pH sensitivity of Zn2+ coordination. Therefore, our system possesses multiple effects in tumor treatment: photothermal therapy with near infrared lighting (NIR), thermosensitive DOX release for chemotherapy, and pH-responsive DOX release to enhance deeper therapy in tumor acidic microenvironment. Our in vivo results provide the evidence that Fe3O4@PDA-Zn2+-DOX NPs upon laser exposure have effective anti-tumor therapeutic activity, indicating this platform is suitable for enhanced chemo-photothermal synergistic tumor therapy.

Doxorubicin-reinforced supramolecular hydrogels of RGD-derived peptide conjugates for pH-responsive drug delivery.

Drug incorporation in hydrogels often brings undesirable effects on the stability or mechanical properties of the system. To address this problem, we report the design and synthesis of a RGD-derived peptide conjugate (1-RGDH) for its co-assembly with a commonly used chemotherapeutic drug, doxorubicin (DOX), that formed electrostatic interactions with the 1-RGDH peptide and reinforced the supramolecular network of nanofibers within the matrix of the hydrogel. The hybrid hydrogel demonstrated excellent viscoelastic and shear-thinning properties that greatly facilitated the development of injectable drug delivery systems. Furthermore, it demonstrated a unique pH responsive release of DOX under weakly acidic conditions, paving ways for the controlled release of drug cargos in a typical tumor microenvironment with mild acidity. Finally, the DOX-incorporated hydrogel exhibited a superior anti-tumor efficacy in non-small-cell lung cancer cells A549 compared to the aqueous solution of free DOX, with an integrin receptor-mediated endocytosis pathway revealed for the cellular uptake of DOX-incorporated nanofibers.

Bacterial magnetosomes-based nanocarriers for co-delivery of cancer therapeutics in vitro.

In recent times, co-delivery of therapeutics has emerged as a promising strategy for treating dreadful diseases such as cancer.Materials and methodsIn this study, we developed a novel nanocarrier based on bacterial magnetosomes (BMs) that co-loaded with siRNA and doxorubicin (DOX) using polyethyleneimine (PEI) as a cross-linker (BMs/DP/siRNA). The delivery efficiency of siRNA as well as the pH-responsive release of DOX, and synergistic efficacy of these therapeutics in vitro were systematically investigated.ResultsThe structure of DOX–PEI (DP) conjugates that synthesized via hydrazone bond formation was confirmed by 1H nuclear magnetic resonance (NMR). The in vitro release experiments showed that the DP conjugate (DOX-loading efficiency – 5.77%±0.08%) exhibited the long-term release behavior. Furthermore, the optimal BMs/DP/siRNA particle size of 107.2 nm and the zeta potential value of 31.1±1.0 mV facilitated enhanced cellular internalization efficiency. Moreover, the agarose gel electrophoresis showed that the co-delivery system could protect siRNA from degradation in serum and RNase A. In addition, the cytotoxicity assay showed that BMs/DP/siRNA could achieve an excellent synergistic effect compared to that of siRNA delivery alone. The acridine orange (AO)/ethidium bromide (EB) double staining assay also showed that BMs/DP/siRNA complex could induce cells in a stage of late apoptosis and nanocomplex located in the proximity of the nucleus.ConclusionThe combination of gene and chemotherapeutic drug using BMs is highly efficient, and the BMs/DP/siRNA would be a promising therapeutic strategy for the future therapeutics.

Polymer Brush Decorated MOF Nanoparticles Loaded with AIEgen, Anticancer Drug, and Supramolecular Glue for Regulating and In Situ Observing DOX Release.

UiO-66-based metal-organic framework nanoparticles functionalized with abundant polycationic segments as polymer brushes on surface are created to load negatively charged functional entities composed of anticancer drug, doxorubicin (DOX), and aggregation-induced emissive luminogen, a tetraphenylethene (TPE) derivative, followed by further modification with cucurbit[7]uril (CB[7]) as a supramolecular glue with the aim of pursuing a pH-responsive release function of the loaded functional components. The subsequent investigations verified the constructed formulation capable of promoting the stability and cellular uptake of the nanoparticles. The fluorescence resonance energy transfer between TPE donor and DOX acceptor enables in situ observation of pH-responsive DOX release. Significantly, CB modification appears to facilitate intracellular release of the DOX payload, eventually accounting for potent cytotoxicity to the treated cells.

Polyion complex hydrogels from chemically modified cellulose nanofibrils: Structure-function relationship and potential for controlled and pH-responsive release of doxorubicin

Herein, we report the fabrication of a polyion complex hydrogel from two oppositely charged derivatives of cellulose nanofibrils (CNF). CNF was produced from dissolving pulp through subsequent periodate oxidation, chemical modification, and microfluidization. Three different durations for periodate oxidation (30 min, 120 min, and 180 min) resulted in three different aldehyde contents. Further, two types of chemical modifications were introduced to react with the resulting aldehydes: chlorite oxidation to yield anionic CNF with carboxylic acid groups (DCC) and imination with Girard’s reagent T to yield cationic CNF containing quaternary ammonium groups (CDAC). Functional group contents were assessed using conductometric titration and elemental analysis, while nanofibril morphologies were assessed using atomic force microscopy (AFM). Longer durations of periodate oxidation did not yield different width profile but was found to decrease fibril length. The formation of self-standing hydrogel through mixing of DCC and CDAC dispersions was investigated. Oscillatory rheology was performed to assess the relative strengths of different gels. Self-standing hydrogels were obtained from mixture of DCC180 and CDAC180 dispersions in acetate buffer at pH 4 and 5 at a low concentration of 0.5% w/w that displayed approximately 10-fold increase in storage and loss moduli compared to those of the individual dispersions. Self-standing gels containing doxorubicin (an anticancer drug) displayed pH-responsive release profiles. At physiological pH 7.4, approximately 65% of doxorubicin was retained past a burst release regime, while complete release was observed within 5 days at pH 4. Biocompatibility of DCC180, CDAC180, and their mixture were investigated through quantification of the metabolic activity of NIH3T3 cells in vitro. No significant cytotoxicity was observed at concentrations up to 900 µg/mL. In short, the nanocellulose-based polyion complex hydrogels obtained in this study are promising nature-derived materials for biomedical applications. Statement of SignificanceWe demonstrate that polyion complex can be formed between two cellulose nanofibrils containing complementary charges. To the best of our knowledge, this is the first time that polyion complex formation between complementarily-modified cellulose nanofibrils has been reported, and the results may lead to new ideas on applications of the very promising nanocellulosic materials. The polyion complex helps form a self-standing network that is demonstrated to provide controlled and pH-responsive release of doxorubicin. Particularly, the report explores the connection between the physical properties of functionalizable nanocellulosic materials and their potential biomedical applications. Thus, the study encompasses several broad fields of materials science and engineering, chemistry, and biomedical science that we believe is in line with the readers’ interests.

Polyaspartic acid-anchored mesoporous silica nanoparticles for pH-responsive doxorubicin release.

BackgroundNanotechnology-based drug delivery systems exhibit promising therapeutic efficacy in cancer chemotherapy. However, ideal nano drug carriers are supposed to be sufficiently internalized into cancer cells and then release therapeutic cargoes in response to certain intracellular stimuli, which has never been an easy task to achieve.ObjectiveThis study is to design mesoporous silica nanoparticles (MSNs)-based pH-responsive nano drug delivery system that is effectively internalized into cancer cells and then release drug in response to lysosomal/endosomal acidified environment.MethodsWe synthesized MSNs by sol-gel method. Doxorubicin (DOX) was encapsulated into the pores as a model drug. Polyaspartic acid (PAsA) was anchored on the surface of mesoporous MSNs (P-MSNs) as a gatekeeper via amide linkage and endowed MSNs with positive charge.ResultsIn vitro release analysis demonstrated enhanced DOX release from DOX-loaded PAsA-anchored MSNs (DOX@P-MSNs) under endosomal/lysosomal acidic pH condition. Moreover, more DOX@P-MSNs were internalized into HepG2 cells than DOX-loaded MSNs (DOX@MSNs) and free DOX revealed by flow cytometry. Likewise, confocal microscopic images revealed that DOX@P-MSNs effectively released DOX and translocated to the nucleus. Much stronger cytotoxicity of DOX@P-MSNs against HepG2 cells was observed compared with DOX@MSNs and free DOX.ConclusionDOX@P-MSNs were successfully fabricated and achieved pH-responsive DOX release. We anticipated this nanotherapeutics might be suitable contenders for future in vivo cancer chemotherapeutic applications.