pH-responsive Drug Delivery Research Articles

A holocellulose framework with anisotropic microchannels for directional assembly of copper sulphide nanoparticles for multifunctional applications

Abstract A holocellulose framework (HCFW) with anisotropic microchannels, which is synthesized via a facile top–down strategy, is demonstrated to be an ideal anisotropic substrate to guide the directional assembly of CuS nanoparticles (CuS NPs) along the walls of microchannels. The oxygen-containing groups on the surface of HCFW and its abundant low tortuosity of channels contribute to the high loading (ca. 22.7 wt%) and homogeneous dispersion of CuS NPs as well as the fast outdiffusion of cytotoxic substances (such as Cu(I)/Cu(II)), hence endowing the composite with an outstanding antibacterial activity which achieves approximatively 100% of growth inhibition ratios for Escherichia coli and Staphylococcus aureus and extremely low minimal inhibitory concentrations of 8 μg mL−1 for these both bacteria. For drug delivery application, the release of doxorubicin hydrochloride (DOX) from CuS NPs@HCFW is well regulated by solution pH. A maximum cumulative release capacity of DOX (78.3%) is achieved at pH of 2.2. The cancer therapy capability of DOX-loaded CuS NPs@HCFW is also validated in vivo. Moreover, CuS NPs@HCFW has a strong antibiotic removal ability (~100% complete removal of ciprofloxacin within 120 min) by virtue of adsorption and catalytic oxidation in the presence of potassium peroxymonosulfate. These inspiring results not only indicate the high potential of CuS NPs@HCFW for antibacterial, pH-responsive drug delivery and antibiotic removal applications, but also provide a new sight for the development of novel anisotropic composites by using anisotropic HCFW for more extensive uses.

PH-Sensitive nanoscale materials as robust drug delivery systems for cancer therapy

Cancer is one of the diseases that have the highest mortality, which threatens the human health. Chemotherapy functions as the most widely used strategy in clinic to treat cancer, still exists urgent problems, like lacking selectivity and causing severe side effects. According to detailed researches on the metabolism, functions and histology of cancer tissues, many different features of cancer are uncovered, like lower pH in microenvironment, abnormal redox level in intracellular compartments and elevated expression level of several enzymes and receptors. Recently, the development of smart nanoparticles that response to tumor specific microenvironment has lighted up hope for selective cancer therapy. Herein, this review mainly focuses on pH-sensitive nanoscale materials for anti-cancer drug delivery. We summarized the formation progress of acidic tumor microenvironment, the mechanism of pH-responsive drug delivery system and nanomaterials that responsive to acidic pH in tumor microenvironment.

A Review on pH and Temperature Responsive Gels in Drug Delivery

Anticancer drugs play important roles in cancer treatment. However, these drugs have many disadvantages such as poor solubility, high toxicity, and serious side effects like hair loss, nausea and vomiting, anemia etc. To overcome these drawbacks, many attempts have been made to develop novel controlled drug delivery systems. They can encapsulate the drug and release it to the cancer site without leaking into other sites. The employment of multi-responsive hydrogels as a drug delivery system have some advantages over other drug delivery systems due to their ease of preparation, high efficiency, high-water content, tunable physical, and biological properties. The most advantages of these hydrogels is the volume phase transitions in their cross-linked three-dimensional networks as exposure to external stimuli such as temperature, pH, pressure, electric field, magnetic field and light. There has been research on other drug delivery systems which can respond to changes in pH and temperature for targeted drug release. Among those,gels have been studied mostly for their dual responsiveness. This provides an update on progress of gel based dual pH and temperature responsive drug delivery systems. Various systems under these categories for targeted and controlled delivery of different classes of drugs such as ant diabetic and antibiotic drugs with special emphasis on anticancer drugs are discussed in this review.

PH-responsive surface charge reversal carboxymethyl chitosan-based drug delivery system for pH and reduction dual-responsive triggered DOX release

A facile approach was established to fabricate the pH-responsive surface charge reversal carboxymethyl chitosan-based drug delivery system for pH and reduction dual-responsive triggered DOX release, with a reduction responsive sheddable shell via facile organic solvent-free co-precipitation method. In the proposed DDS, DOX was loaded in the pH responsive core of the poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) fragments, which were bioreducibly conjugated onto the PEGylated carboxymethyl chitosan (PEG-CMCS) backbone as reduction responsive sheddable shielding shell. The proposed PEG-CMCS-SS-PDPA/DOX nanoparticles, with a high drug loading capacity of >36 % with drug-loading only in their cores, showed excellent pH and reduction dual-responsive triggered disintegration and DOX release performance with cumulative release >85 % in the simulated tumor intracellular microenvironment but a low drug leakage <8.5 % in the simulated normal physiological medium within 57 h, lower than all the reported CMCS-based DDSs.

Expansile Nanoparticles Encapsulate Factor Quinolinone Inhibitor 1 and Accumulate in Murine Liver upon Intravenous Administration.

Expansile nanoparticles (eNPs) are a promising pH-responsive polymeric drug delivery vehicle, as demonstrated in multiple intraperitoneal cancer models. However, previous delivery routes were limited to intraperitoneal injection and to a single agent, paclitaxel. In this study, we preliminarily evaluate the biodistribution and in vivo toxicity of eNPs in mice after intravenous injection. The eNPs localize predominantly to the liver, without detectable acute toxicity in the liver or other key organs. On the basis of these results, we encapsulated FQI1, a promising lead compound for treatment of hepatocellular carcinoma, in eNPs. eNPs are taken up by cancerous and noncancerous human liver cells in vitro, although at different rates. FQI1-loaded eNPs release FQI1 in a pH-dependent manner and limit proliferation equivalently to unencapsulated FQI1 in immortalized hepatocytes in vitro. eNPs are a versatile platform delivery system for therapeutic compounds and have potential utility in the treatment of liver disease.

PH-Sensitive Mixed Micelles Assembled from PDEAEMA-PPEGMA and PCL-PPEGMA for Doxorubicin Delivery: Experimental and DPD Simulations Study.

To decrease critical micelle concentration (CMC), improve stability, and keep high drug-loading capacity, three pH-sensitive mixed micelles applied for anticancer drug controlled delivery were prepared by the mixture of polymers poly (N,N-diethylaminoethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) (PDEAEMA-PPEGMA) and polycaprolactone-b-poly (poly(ethylene glycol) methyl ether methacrylate) (PCL-PPEGMA), which were synthesized and confirmed by 1H NMR and gel permeation chromatographic (GPC). The critical micelle concentration (CMC) values of the prepared mixed micelles were low, and the micellar sizes and zeta potentials of the blank mixed micelles demonstrated good pH-responsive behavior. Combined experimental techniques with dissipative particle dynamics (DPD) simulation, the particle sizes, zeta potentials, drug loading content (LC), encapsulation efficiency (EE), aggregation morphologies, and doxorubicin (DOX) distribution of the mixed micelles were investigated, and the high DOX-loading capacity of the mixed micelles was found. Both in vitro DOX release profiles and DPD simulations of the DOX dynamics release process exhibited less leakage and good stability in neutral conditions and accelerated drug release behavior with a little initial burst in slightly acidic conditions. Cytotoxicity tests showed that the polymer PDEAEMA-PPEGMA and the blank mixed micelles had good biocompatibility, and DOX-loaded mixed micelles revealed certain cytotoxicity. These results suggest that the drug-loaded mixed micelles that consisted of the two polymers PDEAEMA-PPEGMA and PCL-PPEGMA can be new types of pH-responsive well-controlled release anticancer drug delivery mixed micelles.

Graphene oxide based functionalized chitosan polyelectrolyte nanocomposite for targeted and pH responsive drug delivery

Graphene oxide (GO) was first modified to amine functionalized GO (AGO) and acts as a cationic polyelectrolyte. Chitosan (CS) was conjugated with folic acid (FA) through N, N´ -Dicyclohexylcarbodiimide coupling to form FA-CS. After this, itaconic acid and acrylic acid monomers are grafted to the hydroxyl group of CS using ethyleneglycol dimethacrylate as cross linker and potassium peroxydisulfate as an initiator to generate –COOH functional groups and forming chemically modified chitosan (CMCS). Further doxorubicin (DOX) loaded into the FA-CMCS/AGO through π-π stacking interactions. The resulting nanocomposite was characterized by FTIR, SEM, TEM, Raman, AFM, DLS and ZP. The drug loading capacity was as high as 95.0% and the drug release rate at pH 5.3 was significantly higher than that under physiological conditions of pH 7.4. Cell viability of L929, HeLa and MCF7 cells was studied. The studies suggest the drug carrier has potential clinical applications for anticancer drug delivery.

Doxorubicin Encapsulated in TPGS-Modified 2D-Nanodisks Overcomes Multidrug Resistance.

Multidrug resistance (MDR) is regarded as a main obstacle for effective chemotherapy, and P-glycoprotein (P-gp)-mediated drug efflux has been demonstrated to be the key factor responsible for MDR. In this study, a novel pH-responsive hybrid drug delivery system was developed by conjugating d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a kind of P-gp inhibitor, on the surface of laponite nanodisks to overcome MDR. The prepared LM-TPGS display excellent colloidal stability, a high encapsulation efficiency of doxorubicin (DOX), and a pH-responsive drug release profile. In vitro experiments verified that LM-TPGS/DOX could exhibit significantly enhanced therapeutic efficacy in treating DOX-resistant breast cancer cells (MCF-7/ADR) through inhibiting the activity of P-gp-mediated drug efflux and effectively accumulating DOX within cancer cells. In vivo results revealed that LM-TPGS/DOX outstandingly suppressed MCF-7/ADR tumors with low side effects. Therefore, the high drug payload, enhanced inhibition efficacy to drug-resistant cells, and low side effects make the LM-TPGS/DOX a promising nanoplatform to reverse MDR for effective chemotherapy.

Synthesis and Characterization of pH-Responsive PEG-Poly(β-Amino Ester) Block Copolymer Micelles as Drug Carriers to Eliminate Cancer Stem Cells

PEG-poly(β-amino ester) (PEG-PBAE), which is an effective pH-responsive copolymer, was mainly synthesized by Michael step polymerization. Thioridazine (Thz), which was reported to selectively eliminate cancer stem cells (CSCs), was loaded into PEG-PBAE micelles (PPM) prepared by self-assembly at low concentrations. The critical micelle concentrations (CMC) of PPM in water were 2.49 μg/mL. The pH-responsive PBAE segment was soluble due to protonated tertiary amine groups when the pH decreased below pH 6.8, but it was insoluble at pH 7.4. The Thz-loaded PEG-PBAE micelle (Thz/PPM) exhibited a spherical shape, and the drug loading was 15.5%. In vitro release of Thz/PPM showed that this pH-sensitivity triggered the rapid release of encapsulated Thz in a weakly acidic environment. The in vitro cytotoxicity and cellular uptake of various formulations at pH 7.4 and 5.5 were evaluated on the mammospheres (MS), which were sorted by MCF-7 human breast cancer cell lines and identified to be a CD44+/CD24− phenotype. The results of the cytotoxicity assay showed that blank micelles were nontoxic and Thz/PPM exhibited a similar anti-CSC effect on MS compared to Thz solution. Stronger fluorescence signal of Coumarin-6 (C6) was observed in MS treated by C6-loaded PPM (C6/PPM) at pH 5.5. The tumor inhibition rate and tumor weight of the free DOX and Thz/PPM groups were significantly different from those of the other groups, which free DOX and Thz/PPM effectively suppressed breast tumor growth in vivo. The above experimental results showed that Thz/PPM is an ideal and effective pH-responsive drug delivery carrier to a targeted therapy of CSCs.

Block copolymer@ZIF-8 nanocomposites as a pH-responsive multi-steps release system for controlled drug delivery

Developing the hybrid nanosystems for controlled drug release is still a challenging task. In this work, pH-responsive core-shell nanocomposites have been prepared by the growth of zeolitic imidazolate framework-8 (ZIF-8) on the surface of polymeric aggregates self-assembled from poly(ε-caprolactone)-block-poly (quaternized vinylbenzyl chloride/bipyridine) (PCL-b-q(PVBC/BPy), BCP for short) in water. The core of the micelles or the inner cavity of vesicles serves as the drug storage reservoir for the doxorubicin hydrochloride (DOX) and the ZIF-8 shells act as the gatekeepers to prevent drug premature release at physiological environment. Upon pH stimulus, the core-shell nanocomposites (BCP@ZIF-8) show a retarded drug release behavior compared with DOX-loaded polymeric aggregates counterparts (without the shell of ZIF-8). Moreover, the as-prepared nanocomposites perform good biocompatibility towards MCF-7 cell. Meanwhile, the DOX-loaded BCP@ZIF-8 nanocomposites present lower cytotoxicity compared with DOX-loaded BCP and free DOX. The confocal microscopy study shows the core-shell nanocomposites could be efficiently internalized by cancer cells, and the loaded DOX could be successfully released under acidic intracellular environment. The above result shows that the core-shell nanocomposite could be a promising candidate for pH-responsive drug delivery system in the cancer therapy.

A pH-Responsive Charge-Reversal Drug Delivery System with Tumor-Specific Drug Release and ROS Generation for Cancer Therapy.

IntroductionPoor cell uptake and incomplete intracellular drug release are the two major challenges for polymeric prodrug-based drug delivery systems (PPDDSs) in cancer treatment.MethodsHerein, a PPDDS with pH-induced surface charge-reversal and reactive oxygen species (ROS) amplification for ROS-triggered self-accelerating drug release was developed, which was formed by encapsulating a ROS generation agent (vitamin K3 (VK3)) in pH/ROS dual-sensitive polymetric prodrug (PEG-b-P(LL-g-TK-PTX)-(LL-g-DMA)) based micelle nanoparticles (denoted as PVD-NPs).ResultsThe surface charge of the PVD-NPs can change from negative to positive for enhanced cell uptake in response to tumor extracellular acidity pH. After internalization by cancer cells, PVD-NPs demonstrate dual drug release in response to intracellular ROS-rich conditions. In addition, the released VK3 can produce ROS under the catalysis by NAD(P)H:quinone oxidoreductase-1, which facilitates tumor-specific ROS amplification and drug release selectively in cancer cells to enhance chemotherapy.ConclusionBoth in vitro and in vivo experiments demonstrated that the PVD-NPs showed significant antitumor activity in human prostate cancer.

Development and evaluation of a pH-responsive and water-soluble drug delivery system based on smart polymer coating of graphene nanosheets: an in silico study.

The objective of this study is to develop a controlled and water-soluble delivery system for doxorubicin (DOX) based on the coating of graphene (G) with a smart polymer. A combination of polyethyleneimine (PEI) and G–DOX is investigated by performing density functional theory (DFT) calculations and molecular dynamics (MD) simulations. Several parameters have been employed to evaluate the effect of PEI on the adsorption and release mechanisms of DOX. The obtained results indicated that the binding energy of the drug molecule on G in the presence of PEI is enhanced by about 20% under neutral conditions, whereas the drug absorption becomes weaker in an acidic environment so that DOX could be separated from the carrier surface using near-infrared radiation (NIR). Based on the atom in molecule (AIM) theory, two hydrogen bonds with strengths of about −12.59 and −39.99 kJ mol−1 have been established. Furthermore, evaluating the dynamic behavior of the designed systems in water solution shows that the polymer in physiological pH rapidly adsorbed on the drug–carrier complex. However, at acidic pH, it is quickly desorbed from the carrier surface and the G–DOX complex can be exposed to cancer cells. The obtained results of the present research may be used in future experimental work to design smart DDSs.

Supramolecular combination chemotherapy: a pH-responsive co-encapsulation drug delivery system.

Most cancer chemotherapy regimens rely on the use of two or more chemotherapeutic agents. However, achieving the best possible dosing of the individual drugs can be challenging due to differences in metabolism, uptake, and clearance among other factors. Here we describe a supramolecular strategy for achieving drug delivery in which the loading ratio of two active components is easily defined. Specifically, we report the formation of aggregates comprised of self-assembled amphiphiles between carboxylatopillar[6]arene (CP6A) and an oxaliplatin (OX)-type Pt(iv) prodrug (PtC10). The association constant (K a) for the underlying host-guest interaction at pH 7.4 ((1.16 ± 0.03) × 104 M-1) is an order of magnitude higher than at pH 5.0 ((1.73 ± 0.15) × 103 M-1). A second chemotherapeutic, doxorubicin (DOX), may be encapsulated in the resulting vesicles (PtC10⊂CP6A) to give a supramolecular combination chemotherapeutic system DOX@PtC10⊂CP6A. Drug release studies served to confirm that PtC10 and DOX are released in acidic environments. Support for a synergistic antiproliferative effect relative to PtC10 + DOX came from cellular studies of DOX@PtC10⊂CP6A using the human liver hepatocellular carcinoma (HepG-2) cell line. In vivo studies revealed that DOX@PtC10⊂CP6A is not only able to retard tumor growth efficiently but also reduce drug-related toxic side effects in BALB/c nude mice bearing HepG-2 subcutaneous tumor xenografts. These favorable findings are attributed to the formation of a ternary complex that benefits from an enhanced permeability and retention (EPR) effect in vivo while allowing for the pH-based release of PtC10 and DOX at the tumor site.

One-pot synthesis of Ln3+-doped porous BiF3@PAA nanospheres for temperature sensing and pH-responsive drug delivery guided by CT imaging.

The design and synthesis of responsive inorganic nanocapsules have attracted intensive research interest in cancer treatment. The combination of non-invasive diagnosis and chemotherapy into a single theranostic nanoplatform is prospective in the biomedical field. In this work, a polyacrylic acid (PAA)-functionalized porous BiF3:Yb,Er nanocarrier was constructed via a straightforward one-pot solvothermal strategy. Compared with the undoped BiF3 sub-microspheres, the lanthanide ion (Ln3+) doping endowed the BiF3 material with a smaller size and increased BET specific surface area and pore volume, which make it suitable as a drug carrier. It was found that the synthesized nanomaterial could effectively relieve the side effects of doxorubicin (DOX) and exhibited pH-dependent DOX loading and release. Its satisfactory biocompatibility and efficient tumor inhibition were emphasized by a series of in vitro/in vivo experiments. In addition, the synthesized nanomaterial exhibited favorable CT contrast efficacy due to the excellent X-ray attenuation coefficient of Bi. Moreover, characteristic upconversion luminescence and temperature sensing in a wide temperature range were realized over the synthesized BiF3:Yb,Er sample. Therefore, carboxyl-functionalized BiF3:Yb,Er can be expected to be an ideal candidate in the fabrication of temperature sensing and multifunctional theranostic nanoplatforms.

Multicompartmental Mesoporous Silica/Polymer Nanostructured Hybrids: Design Capabilities by Integrating Linear and Star-Shaped Block Copolymers.

Poly(2-vinyl pyridine)-b-poly(ethylene oxide) (P2VP-b-PEO) linear diblock copolymer and polystyrene–poly(ethylene oxide) (PS10PEO10) heteroarm star copolymer were used as building elements to prepare organic–inorganic hybrids. By using the layer-by-layer (LbL) methodology, these elements were integrated on mesoporous silica through non-covalent interactions, namely, ionic and H-bonding. For the latter, tannic acid (TA) was used as an intermediate layer. The deposition of the various layers was monitored by thermogravimetric analysis (TGA), electrophoretic measurements, and confocal microscopy. The final silica hybrid, bearing alternating P2VP-b-PEO and PS10PEO10 star layers was capable of carrying one hydrophilic and two hydrophobic chemical species in distinct compartments. These multicompartmental organic–inorganic hybrids could be used as nanostructured carriers for pH-responsive multiple drug delivery and potential theranostic applications.

Design of Metal-Organic Frameworks for pH-Responsive Drug Delivery Application

Metal-Organic Frameworks (MOFs) have aroused great interest in the field of nanoscience and nanotechnology particularly in biomedical domains, such as Drug Delivery System (DDS), Biomedical Imaging (BI) and Photodynamic Therapy (PDT). As an emerging material, MOFs possess extraordinarily high surface area, controllable particle size and good biocompatibility. With extraordinary flexibility in the selection of organic and inorganic components, MOFs can rationally be tuned to obtain the materials having versatile structures and porosities. MOFs can serve as ideal vehicles for DDS, BI and PDT through modification and function. In this review, we summarized the design and synthetic strategies for preparing MOFs and introduced their recent advanced usage in DDS, BI and PDT. Finally, the prospect and future challenges of these nanomaterials are also documented.

Metal-Phenolic Network-Coated Hyaluronic Acid Nanoparticles for pH-Responsive Drug Delivery.

Although self-assembled nanoparticles (SNPs) have been used extensively for targeted drug delivery, their clinical applications have been limited since most of the drugs are released into the blood before they reach their target site. In this study, metal-phenolic network (MPN)-coated SNPs (MPN-SNPs), which consist of an amphiphilic hyaluronic acid derivative, were prepared to be a pH-responsive nanocarrier to facilitate drug release in tumor microenvironments (TME). Due to their amphiphilic nature, SNPs were capable of encapsulating doxorubicin (DOX), chosen as the model anticancer drug. Tannic acid and FeCl3 were added to the surface of the DOX-SNPs, which allowed them to be readily coated with MPNs as the diffusion barrier. The pH-sensitive MPN corona allowed for a rapid release of DOX and effective cellular SNP uptake in the mildly acidic condition (pH 6.5) mimicking TME, to which the hyaluronic acid was exposed to facilitate receptor-mediated endocytosis. The DOX-loaded MPN-SNPs exhibited a higher cytotoxicity for the cancer cells, suggesting their potential use as a drug carrier in targeted cancer therapy.

Fabrication of pH-responsive PAA-NaMnF3@DOX hybrid nanostructures for magnetic resonance imaging and drug delivery

The combination of diagnosis and treatment is considered as a promising strategy to improve the efficiency of cancer treatment. Here, the authors report an intelligent theranostic nanoplatform that combines diagnosis and chemotherapy based on the NaMnF3 nanoparticles (NPs). Poly (acrylic acid) (PAA) modified NaMnF3 NPs (PAA-NaMnF3 NPs) were synthesized by a facile and low cost reaction method. Doxorubicin hydrochloride (DOX)-loaded PAA-NaMnF3 (PAA-NaMnF3@DOX) hybrid nanostructures have been successfully developed via electrostatic interaction for dual-functional magnetic resonance imaging (MRI) and pH-responsive drug delivery. The obtained PAA-NaMnF3@DOX hybrid nanostructures could not only act as T1 and T2-weighted contrast agents for MRI as a result of the existence of Mn2+ ions but also exhibit a pH-responsive drug releasing behavior, which brings an obvious cytotoxicity to cancer cells via MTT assay. The endocytosis process of PAA-NaMnF3@DOX hybrid nanostructures was further evaluated using optical microscopy. These results demonstrate that the developed PAA-NaMnF3@DOX hybrid nanostructures as a multifunctional theranostic nanoplatform could serve as imaging contrast agents and drug delivery system for cancer imaging and therapy.

Fabrication and Antitumor Mechanism of a Nanoparticle Drug Delivery System: Graphene Oxide/Chitosan Oligosaccharide/γ‐Polyglutamic Acid Composites for Anticancer Drug Delivery

AbstractThis study focused on the design of a novel pH responsive nanoparticle drug delivery system (NDDS) with high biocompatibility and water solubility. The designed system was used for doxorubicin (DOX) delivery at tumor sites in a controlled manner. These innovative nanoparticles are soluble in physiological solutions besides water. In this study, pretreated γ‐polyglutamic acid (γ‐PGA) aqueous solutions were loaded into composites of graphene oxide (GO) covalently linked with chitosan oligosaccharide (CO) to fabricate GO‐CO‐γ‐PGA via amidation. The characterizations of the synthesized samples were carried out by using fourier transform infrared spectrometer (FTIR), X‐ray photoelectron spectrometer (XPS), ultraviolet– visible spectrophotometer (UV‐Vis), transmission electron microscopy (TEM), atomic force microscope (AFM) and zeta potential. Furthermore, drug loading and release behaviors from GO‐CO‐γ‐PGA were studied. The DOX loading in the constructed nanocarriers (GO‐CO‐γ‐PGA‐DOX) resulted in controlled and sustained release. The results of cell experiments revealed that the synthesized composites, which were easily transferred into cells, showed low toxicity and exhibited excellent antitumor effect due to its good connection with DOX. In addition, the composite nanoparticles caused the cell cycle arrest of Hela cells at the G2/M phase. Western blot results indicated that GO‐CO‐γ‐PGA‐DOX downregulated the expression of Bcl‐2 protein but upregulated Bax protein expression, which triggered the release of cytochrome C (Cytc). This condition further activated caspase‐3, cleaved the substrate of poly ADP‐ribose polymerase (PARP), and caused cell apoptosis. These results demonstrated that GO‐CO‐γ‐PGA‐DOX induces apoptosis via the intrinsic mitochondrial apoptotic pathway. Hence GO‐CO‐γ‐PGA composites have promising application in the field of biomedicine.

PH-responsive hydrogels based on the self-assembly of short polypeptides for controlled release of peptide and protein drugs

In this study, a pH-responsive hydrogel consisting of a 4-arm poly(ethylene glycol)-block-poly(L-glutamic acid) (4a-PEG-PLG) copolymer was developed and used for the controlled release of peptide and protein drugs. It was found that the mechanical properties and degradation processes of the hydrogels could be tuned by changing the polymer concentrations. In vitro drug release results revealed that the release of insulin (or BSA) from hydrogel was highly dependent on the pH, i.e., less than 20% of insulin (or BSA) was released in the artificial gastric fluid (AGF) at 72 h, while close to 100% of insulin (or BSA) was released in the artificial intestinal fluid (AIF). It was because that the deprotonation of carboxyl groups in PLG block caused the disassembly, and even disintegration of the hydrogel in AGF, thereby resulting in accelerated drug release. Circular dichroism spectra showed that the bioactivities of insulin and BSA released from hydrogels were obviously unchanged compared to those of native insulin and BSA, respectively. Mouse fibroblast L929 cells were cultured on the surface of hydrogels and the viabilities of cultured cells were above 90% after incubation for 24 h, indicating that the hydrogels had good cytocompatibilities. Moreover, in vivo degradation evaluation disclosed that the formed hydrogels will completely degrade after 8 days, and the H&E staining study demonstrated the excellent biocompatibility of the as-prepared hydrogels. Therefore, the biocompatible and biodegradable 4a-PEG-PLG hydrogel may serve as a promising platform for pH-responsive drug delivery.