pH-responsive Doxorubicin Research Articles

Ferrocene-functionalized magnetic core-shell nanoparticles based on hydrosilylation reaction for pH-responsive doxorubicin delivery system

This study describes the development of an innovative pH-sensitive drug delivery system (DDS) utilizing ferrocene (Fc) and magnetic nanoparticles (MNPs) for cancer therapy. One potential method for generating a diverse range of functional NPs involves attaching functional substances to MNPs. In this investigation, we display the successful modification of Fe3O4 NPs by an Fc derivative (4-Ferrocenylbutyl)dimethylsilane through a hydrosilylation reaction toward the synthesis of the Fe3O4@SiO2@VTES@Fc nanocarrier (NC). The doxorubicin (DOX) drug was loaded onto Fe3O4@SiO2@VTES@Fc NC with a drug loading capacity of about 80 % via π-π stacking interactions. Also, the prepared materials were thoroughly characterized using FT-IR, XRD, FE-SEM, EDX-MAP, VSM, DAPI, MTT, antioxidants, and CV techniques. In vitro studies on the release of DOX from Fe3O4@SiO2@VTES@Fc NC indicated a pH-responsive behavior with a lower release rate (< 10 %) at pH 7.4 compared to pH 5 (approximately 70 %) over a period of 96 h. Moreover, cytotoxicity assessments demonstrated notable cytotoxic effects of DOX-loaded Fe3O4@SiO2@VTES@Fc on MCF-7 cells (IC50 value: ∼8 µg/mL). The study findings suggest that the fabricated magnetic core-shell NC (Fe3O4@SiO2@VTES@Fc/DOX) exhibits stimulus-responsive behavior and holds promise as a sophisticated approach to specifically transport therapeutic agents into tumor sites while minimizing exposure to healthy tissues.

Magnetic alginate core-shell nanoparticles based on Schiff-base imine bonding for pH-responsive doxorubicin delivery system

This research describes the development of a novel pH-responsive drug delivery system (DDS) based on sodium alginate (SA) and magnetic nanoparticles (MNPs) for cancer treatments. One possible approach to creating a wide variety of functional nanoparticles is to graft functional materials onto magnetite nanoparticles. In this study, we demonstrate the effective alteration of Fe3O4 nanoparticles using the alginate dialdehyde (ADA) group through a Schiff-Base imine reaction toward synthesizing Fe3O4@SiO2@APTMS@ADA (FSA@ADA) nanocarrier (NC). doxorubicin (DOX) as an anticancer drug was loaded (about 93 % drug loading capacities) on the FSA@ADA NC through chemical and physical interactions. doxorubicin (DOX) as an anticancer drug was loaded (about 93 % drug loading capacities) on the FSA@ADA NC through chemical and physical interactions. The synthesized nanocarriers were thoroughly characterized by various techniques, including FT-IR, FE-SEM, EDX-MAP, TEM, XRD, VSM, TGA, and 1HNMR. In vitro DOX release studies showed a pH-dependent manner and its release rate is lower (< 15 %) at 7.4 than pH 5 (about 75 %) over 25 days. Cytotoxicity results showed good biocompatibility for blank FSA@ADA (over about 85 % cell viability), whereas DOX-loaded FSA@ADA NCs had higher cytotoxic effects (IC50 value: ∼6 µg/mL) as a result of the controlled release of DOX into HeLa cells. Results showed that the magnetic core-shell FSA@ADA/DOX NC has the potential to be used as a targeted stimuli-responsive drug for cancer treatment.

Pharmacokinetic-Pharmacodynamic Analysis of pH-Responsive Doxorubicin-Releasing Micelles with Anticancer Activity.

This study aimed to investigate the effect of in vivo pH-responsive doxorubicin (DOX) release and the targetability of pilot molecules in folic acid (FA)-modified micelles using a pharmacokinetic-pharmacodynamic (PK-PD) model. The time profiles of intratumoral DOX concentrations in Walker256 tumor-bearing rats were monitored using a microdialysis probe, followed by compartmental analysis, to evaluate intratumoral tissue pharmacokinetics. Maximal DOX was released from micelles 350 min after the administration of pH-responsive DOX-releasing micelles. However, FA modification of the micelles shortened the time to peak drug concentration to 150 min. Additionally, FA modification resulted in a 27-fold increase in the tumor inflow rate constant. Walker256 tumor-bearing rats were subsequently treated with DOX, pH-responsive DOX-releasing micelles, and pH-responsive DOX-releasing FA-modified micelles to monitor the tumor growth-time profiles. An intratumoral threshold concentration of DOX (55-64 ng/g tumor) was introduced into the drug efficacy compartment to construct a PD model, followed by PK-PD analysis of the tumor growth-time profiles. Similar results of threshold concentration and drug potency of DOX were obtained across all three formulations. Cell proliferation was delayed as the drug delivery ability of DOX was improved. The PK model, which was developed using the microdialysis method, revealed the intratumoral pH-responsive DOX distribution profiles. This facilitated the estimation of intratumoral PK parameters. The PD model with threshold concentrations contributed to the estimation of PD parameters in the three formulations, with consistent mechanisms observed. We believe that our PK-PD model can objectively assess the contributions of pH-responsive release ability and pilot molecule targetability to pharmacological effects.

A self-healable and injectable hydrogel for pH-responsive doxorubicin drug delivery in vitro and in vivo for colon cancer treatment

Hydrogels are three-dimensional solid-like structures with a wide range of applications in drug transport, tissue engineering, wound dressing, etc. We developed herein a new hydrogel by mixing 5′-guanosine monophosphate (5′-GMP) disodium salt (16 mM) and 1,4,5,8-naphthalene tetracarboxylic acid tetra potassium salt (NAP) (4 mM) in 4:1 (GMP:NAP) stoichiometry in aqueous media (pH ∼4 at 25 °C). The mechanical properties of the resulting hydrogel were investigated by rheological studies, which showed that the hydrogel formed at pH 4 is the most stable [storage modulus (Gꞌ) of ∼4000 Pa] and has higher endurance for the oscillatory strain (20% strain). Spectroscopic investigations provided insights into the unique self-assembly of 5′-GMP and NAP. Further, the composite exhibited pH-responsive hydrogelation over the pH range of 3–6, and the gel was transformed into a sol form at pH > 5. This stimuli-sensitive nature of the hydrogel was then exploited for the encapsulation and efficacious delivery of an anticancer drug, doxorubicin (DOX), specifically toward the colorectal cancer. Microscopic studies revealed the presence of a regular entangled fibrillar network for the hydrogels, which allowed for its exceptionally high drug loading capacity. The controlled release of DOX from the hydrogel was then studied at the physiological pH of the gastrointestinal tract, i.e. pH ∼7.4. The DOX-loaded hydrogel (DOX-Gel) exhibited a ∼82% release of DOX over 100 h at pH ∼7.4. The enhanced cellular toxicity of DOX was observed in CT-26 murine colorectal carcinoma cell lines treated with the DOX-loaded hydrogel compared to DOX only as manifested from the fluorescence-activated cell sortinganalyses and fluorescence microscopic studies. The fluorescence-activated cell sorting analysis showed a ∼4.5-fold increase in the drug internalization for the DOX-Gel as compared to DOX only formulations. The co-localization of DOX into the cell nucleus was confirmed from confocal microscopy. The in vivo drug delivery efficacy of this pH-responsive hydrogel was further assessed on an animal tumor model, Balb/c mice (n = 9). A significant regression of ∼87.5% in the tumor volume was observed after 21 days of DOX-gel administration, in contrast to DOX only formulation, which showed only a ∼46.0% regression in the tumor volume. The blood reports of the non-treated control mice and the mice treated with DOX only indicated a metastatic behavior in comparison with the mice treated with the DOX-Gel. This, the present system, is a self-healable, injectable hydrogel, which makes it an ideal drug delivery vehicle with stimuli-responsive controlled drug release capabilities even in vivo.

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.

Ginsenoside Rg3 Reduces the Toxicity of Graphene Oxide Used for pH-Responsive Delivery of Doxorubicin to Liver and Breast Cancer Cells.

Doxorubicin (DOX) is extensively used in chemotherapy, but it has serious side effects and is inefficient against some cancers, e.g., hepatocarcinoma. To ameliorate the delivery of DOX and reduce its side effects, we designed a pH-responsive delivery system based on graphene oxide (GO) that is capable of a targeted drug release in the acidic tumor microenvironment. GO itself disrupted glutathione biosynthesis and induced reactive oxygen species (ROS) accumulation in human cells. It induced IL17-directed JAK-STAT signaling and VEGF gene expression, leading to increased cell proliferation as an unwanted effect. To counter this, GO was conjugated with the antioxidant, ginsenoside Rg3, prior to loading with DOX. The conjugation of Rg3 to GO significantly reduced the toxicity of the GO carrier by abolishing ROS production. Furthermore, treatment of cells with GO-Rg3 did not induce IL17-directed JAK-STAT signaling and VEGF gene expression-nor cell proliferation-suggesting GO-Rg3 as a promising drug carrier. The anticancer activity of GO-Rg3-DOX conjugates was investigated against Huh7 hepatocarcinoma and MDA-MB-231 breast cancer cells. GO-Rg3-DOX conjugates significantly reduced cancer cell viability, primarily via downregulation of transcription regulatory genes and upregulation of apoptosis genes. GO-Rg3 is an effective, biocompatible, and pH responsive DOX carrier with potential to improve chemotherapy-at least against liver and breast cancers.

Metal-organic-framework-based pyroptosis nanotuner with long blood circulation for augmented chemotherapy.

Pyroptosis is a proinflammatory form of cell death mediated by members of the gasdermin family, and is a powerful tool against cancer. Herein, a pH-responsive doxorubicin (DOX)-encapsulating zeolitic imidazolate framework-8 (ZIF-8) nanoparticle coated with a carboxybetaine-based zwitterionic polymer (DOX@ZIF-8@PCBMA) was prepared. Furthermore, decitabine (DAC) was loaded to obtain a pyroptosis nanotuner (DOX@ZIF-8@PCBMA-DAC). This nanotuner displayed extended blood circulation and enhanced tumor accumulation. In addition, the ZIF-8 structure and disulfide-crosslinked PCBMA coating endowed DOX@ZIF-8@PCBMA-DAC with acidic-pH- and glutathione-responsive degradation. The nanotuner could robustly activate caspase-3 to induce gasdermin E (GSDME)-dependent pyroptosis via the sustained release of DAC and DOX, contributing to excellent tumor suppression with negligible side effects, which may provide novel insights into traditional chemotherapy.

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.

Tumor-associated macrophage membrane-camouflaged pH-responsive polymeric micelles for combined cancer chemotherapy-sensitized immunotherapy

The low immunogenicity and tumor immunosuppressive microenvironment (TIM) are two major obstacles for cancer immunotherapy. Synergistically immunogenic cell death induction and tumor-associated macrophages depletion could perfectly overcome this limitation. Herein, a tumor-associated macrophage (TAMs) membrane-camouflaged pH-responsive doxorubicin (DOX) loaded hyaluronic acid (HA)-g-poly (histidine) polymeric micelles (DHP@M2) was fabricated for the first time. DHP@M2 could effectively accumulated into tumor regions via TAMs membrane mediated immune camouflage. In acidic tumor microenvironment, particle size of DHP was enlarged due to decrease hydrophobic interaction of inner core, which caused a “membrane escape effect” to expose inner HA residue. Together high expression of α4β1 integrin, DHP@M2 could reach CD44/VCAM-1 dual-targetability to facilitate intracellular DOX accumulation for efficient ICD induction. Meanwhile, TAMs membrane could absorb colony stimulating factor 1(CSF1) through high expression of its receptor (CSF1R) on TAMs membrane to deplete TAMs in tumor tissues and relieved TIM. This strategy could efficiently induce cytotoxic T lymphocyte (CTLs) infiltration for antitumor immune response and inhibit tumor progression in 4T1 tumor bearing Balb/c mice. Therefore, DHP@M2 is suitable for cancer chemotherapy-sensitized immunotherapy.

Preparation of Ph-Responsive Vesicular Doxorubicin: Evidence from In-Vitro and in Silico Evaluations

Preparation of Ph-Responsive Vesicular Doxorubicin: Evidence from In-Vitro and in Silico Evaluations

PH-Responsive doxorubicin delivery using shear-thinning biomaterials for localized melanoma treatment.

Injectable shear-thinning biomaterials (STBs) have attracted significant attention because of their efficient and localized delivery of cells as well as various molecules ranging from growth factors to drugs. Recently, electrostatic interaction-based STBs, including gelatin/LAPONITE® nanocomposites, have been developed through a simple assembly process and show outstanding shear-thinning properties and injectability. However, the ability of different compositions of gelatin and LAPONITE® to modulate doxorubicin (DOX) delivery at different pH values to enhance the effectiveness of topical skin cancer treatment is still unclear. Here, we fabricated injectable STBs using gelatin and LAPONITE® to investigate the influence of LAPONITE®/gelatin ratio on mechanical characteristics, capacity for DOX release in response to different pH values, and cytotoxicity toward malignant melanoma. The release profile analysis of various compositions of DOX-loaded STBs under different pH conditions revealed that lower amounts of LAPONITE® (6NC25) led to higher pH-responsiveness capable of achieving a localized, controlled, and sustained release of DOX in an acidic tumor microenvironment. Moreover, we showed that 6NC25 had a lower storage modulus and required lower injection forces compared to those with higher LAPONITE® ratios. Furthermore, DOX delivery analysis in vitro and in vivo demonstrated that DOX-loaded 6NC25 could efficiently target subcutaneous malignant tumors via DOX-induced cell death and growth restriction.

Synthesis of Monodisperse ZIF-67@CuSe@PVP Nanoparticles for pH-Responsive Drug Release and Photothermal Therapy.

In recent years, the combination treatment of chemotherapy and photothermal therapy (PTT) has emerged as an efficient approach to improve anticancer activity. Here, we combine zeolitic imidazolate framework-67 (ZIF-67) and CuSe to build a multifunctional therapeutic platform (ZIF-67@CuSe@PVP) with an efficient chemo-photothermal therapy for cancer treatment. ZIF-67@CuSe@PVP nanoparticles were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), dynamic light scattering (DLS), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), UV-vis, Fourier transform infrared (FT-IR), and nitrogen adsorption-desorption isotherms. These nanoparticles exhibited excellent pH-responsive doxorubicin hydrochloride (DOX) releases due to the decomposition of ZIF-67 and excellent photothermal conversion efficiency (36%) without apparent deterioration during three cycles. In vivo biodistribution evaluation revealed the passive tumor-targeting ability of ZIF-67@CuSe@PVP@DOX via the enhanced permeability and retention (EPR) effect. Both in vitro and in vivo data demonstrated excellent anticancer efficacy of ZIF-67@CuSe@PVP in tumor-bearing mice. This multifunctional therapeutic platform could have certain clinical application potential.

Sequentially pH-Responsive Drug-Delivery Nanosystem for Tumor Immunogenic Cell Death and Cooperating with Immune Checkpoint Blockade for Efficient Cancer Chemoimmunotherapy.

Chemoimmunotherapy has anchored a new blueprint for cancer management. As a burgeoning approach, immunotherapy has shifted the paradigm of traditional chemotherapy and opened up new prospects for cancer treatment. Here, a sequentially pH-responsive doxorubicin (DOX) delivery nanosystem is designed for simultaneous chemotherapy and tumor immunogenic cell death (ICD). DOX is modified into pH-sensitive cis-aconityl-doxorubicin (CAD) for being easily adsorbed by polycationic polyethylenimine (PEI), and the PEI/CAD complexes are in situ-shielded by aldehyde-modified polyethylene glycol (PEG). The PEG/PEI/CAD nanoparticles (NPs) can keep stable in neutral physiological pH during systemic circulation but will detach PEG shielding once in slightly acidic tumor extracellular pH. The exposed positive PEI/CAD complexes are endocytosed effortlessly, and CAD is then converted back to DOX by endosomal-acidity-triggered cis-aconityl cleavage. The released DOX further elicits ICD, and the moribund tumor cells will release antigens and damage-associated molecular patterns to recruit dendritic cells and activate antitumor immunity. An excellent therapeutic effect is achieved when the immune checkpoint PD-1 antibody (aPD-1) is utilized to cooperate with the PEG/PEI/CAD NPs for blocking tumor immune escape and maintaining antitumor activity of the ICD-instigated T cells. The sequentially pH-responsive DOX delivery nanosystem cooperating with immune checkpoint blockade will provide a potential strategy for cancer chemoimmunotherapy.

Synthesis and surface modification of mesoporous metal-organic framework (UiO-66) for efficient pH-responsive drug delivery and lung cancer treatment

This paper applied mesoporous metal-organic frameworks (MOFs) of UiO-66 particles for pH-responsive doxorubicin (DOX) delivery and cancer treatment. Mesoporous structured UiO-66 MOFs were synthesized, and carboxymethylcellulose (CMC) was loaded for sensitive pH response and also as a linker to encapsulate the chemotherapeutic drug of DOX. The composite of UiO-66/CMC@DOX was synthesized, and the loading capacity was as high as 45 μg DOX per mg of the carrier. The structure and crystalization of the UiO-66 MOFs were determined by the Transmitting Electron Microscope (TEM) and x-ray diffraction methods, while the loading of CMC and DOX was inspected by Fourier Transform InfraRed (FT-IR) and UV–vis spectroscopy. The DOX release from UiO-66/CMC@DOX was tested under different pH at 37 °C. The DOX accumulative release could reach 78% under the pH of 5. A lower pH was more favorable for DOX release due to the CMC shrinking and higher DOX solubility in an acidic environment. The cytotoxicity study indicated that, under the DOX concentration of 4 μg ml−1, the A549 cell (Lung Carcinoma Cell Line) viability of UiO-66/CMC was 28%, which was lower than that from free DOX solution (47%). UiO-66 MOFs were demonstrated to be an efficient drug delivery carrier for chemotherapeutic drug and release.

Fluorescence resonance energy transfer monitoring of pH-responsive doxorubicin release from carbon dots/aptamer functionalized magnetic mesoporous silica.

Aim: To develop a novel theranostic nanoplatform for simultaneous fluorescent monitoring and stimuli-triggered drug delivery. Materials & methods: Different microscopic and spectroscopic techniques were used for the characterization of nanocarriers. MCF-7 and human umbilical vein endothelial cell lines were cultured and treated with different doses of doxorubicin-loaded nanocarriers. The cell viability and drug release were studied using MTT assay and fluorescence microscopy. Results: Biocompatible and mono-disperse nanocarriers represent hollow and mesoporous structures with the calculated surface area of 552.83m2.g-1, high magnetic activity (12.6 emu.g-1), appropriate colloidal stability and high drug loading capacity (up to 61%). Conclusion: Taxane-based carbon dots act as the pH-responsive gatekeepers for the controlled release of doxorubicin into cancer cells and provide a fluorescence resonance energy transfer system for real-time monitoring of drug delivery.

Formaldehyde-doxorubicin dual polymeric drug delivery system for higher efficacy and limited cardiotoxicity of anthracyclines

We report the synthesis of a dual delivery system composed of chemically bound pH-responsive formaldehyde polymer prodrugs and pH-responsive doxorubicin loaded nanoparticles to increase the therapeutic index of doxorubicin by working in synergy with formaldehyde to enable the formation of DOX-DNA adducts and limiting the cardiotoxicity of anthracyclines. Polyacrylates bearing 1,2- and 1,3- pendant diols were synthesized via reversible addition fragmentation chain transfer (RAFT) polymerization to conjugate formaldehyde, forming 5- or 6-membered acetal rings with tunable conjugation percentages (1.5–10 wt%) for controlled release in acidic environments of the tumor extracellular matrix. The formaldehyde-conjugated prodrugs are then combined with polyester nanoparticles formed by intermolecular crosslinking via oxime click chemistry of less than 200 nm in size containing 14 wt% encapsulated Doxorubicin (DOX). Release kinetics show a sustained release of both DOX and formaldehyde at pH 5.0, mimicking the low pH of the tumor environment whereas insignificant release was recorded at physiological pH. The cell viability of the dual delivery system combination was evaluated in 4 T1 breast cancer cells resulting in a considerably increase of cell death of about 4-fold compared to free DOX alone. The protective effect of formaldehyde towards DOX- induced damages was observed in Lactate dehydrogenase assays with cardiomyocytes (P1-3). The resulting polymeric delivery system is the first reported example of a DOX and formaldehyde co-administration, demonstrating the potential significant effect of formaldehyde towards an improved anti-cancer efficacy and reduced cardiotoxicity of DOX.

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.

The toxicity performance of pH-responsive doxorubicin nanocarrier with different drug loading strategy

To improve the water solubility, keep drug loading rate and reduce toxic side effects of chemotherapeutic drugs, two kinds of pH–responsive nanoparticles (denoted as HDOX and PDOX) were prepared to achieve controlled release of drugs and their toxicity against tumor cells were studied. The HDOX was synthesized to incorporate doxorubicin (DOX) via a pH-responsive chemical hydrazone bond, while the PDOX was a pH-responsive polymer-coated nanoparticle to load DOX. The drug loading was measured by fluorescence spectroscopy. The drug release performances in vitro were investigated under different simulated conditions, as well as the toxicity of two NPs were evaluated by the MTT assay. In vitro experiments showed that HDOX (∼15 wt %) has a superior drug-loading ratio compared to PDOX (∼10 wt %). Besides, HDOX and PDOX also displayed a higher stability in normal physiological environment. After the nanoparticles were internalized by the tumor cells, the nanoparticles could transport to the entire tumor cells and showed a pH-responsive drug release behavior. In vivo experiments confirmed excellent biological safety of the two nanoparticles. These results demonstrated that nanocarrier-based chemical bonding strategy provided advantages for the development pH-responsive nanomedicine for cancer therapy.

Injectable biodegradation-visual self-healing citrate hydrogel with high tissue penetration for microenvironment-responsive degradation and local tumor therapy

Local tumor therapy through injectable biodegradable hydrogels with controlled drug release has attracted much attention recently, due to their easy operation, low side effect and efficiency. However, most of the reported therapeutic hydrogel system showed a lack of biodegradation tracking and tumor environment-responsive degradation/therapy. Herein, we developed a multifunctional injectable biodegradation-visual citric acid-based self-healing scaffolds with microenvironment-responsive degradation and drug release for safe and efficient skin tumor therapy (FPRC hydrogel). FPRC scaffolds possess multifunctional properties including thermosensitive, injectable, self-healing, photoluminescent and pH-responsive degradation/drug release. The FPRC scaffolds with strong red fluorescence which has good photostability, tissue penetration and biocompatibility can be tracked and monitored to evaluate the degradation of the scaffolds in vivo. Moreover, the FPRC scaffolds showed pH-responsive doxorubicin (DOX) release, efficiently killed the A375 cancer cell in vitro and suppressed the tumor growth in vivo. Compared to the free drug (DOX), the FPRC@DOX scaffolds displayed a significantly high therapeutic effect and less biotoxicity. This work provides an alternative strategy to design smart visual scaffolds for tumor therapy and regenerative medicine.

Preparation of pH-Responsive Doxorubicin Nanocapsules by Combining High-gravity Antisolvent Precipitation with In-situ Polymerization for Intracellular Anticancer Drug Delivery

Owing to the low pH value in tumor and cancer cells, drug delivery systems based on pH-responsive polymer nanocarriers have been extensively explored for anticancer chemotherapy. Herein, we developed a pH-responsive doxorubicin(DOX) nanocapsule(named as DNanoCapsule) prepared by combining in-situ polymerization technique with high-gravity antisolvent precipitation technique through an amphiphilic polymerized surface ligand. DNanoCapsules show an obvious spherical core-shell structure with a single DOX nanoparticle encapsulated in the polymer layer. Dissolution rate studies prove that the DNanoCapsules have robust drug-release profiles under acidic environments due to the division of the pH-sensitive cross-linker, which triggers the collapse of the polymer layer. The in vitro investigations demonstrated that the DNanoCapsules exhibited high cellular uptake efficiency and cytotoxicity for both HeLa and MCF-7 cancer cells. Therefore, this work may provide a promising strategy to design and develop various stimuli-responsive drug nanocapsules for the treatment of cancer or other diseases.