Release Of Biomacromolecules Research Articles

Acid-Responsive Macroporous Silica Nanoparticles for Bcl-2-Functional-Converting Peptide Release and Synergism with Celastrol for Enhanced Therapy against Resistant Cancer.

Combination of chemotherapeutics with polypeptide/protein drugs has been demonstrated to be an effective approach for treatment against cancer multidrug resistance. However, due to the low biostability and weak cell penetrating ability of biomacromolecules, intracellular delivery and release of biomacromolecules in a spatiotemporally controllable manner in target sites in vivo face great challenges, and synergistic effects will not be achieved as expected just by simple drug combination. Here, we conceived an inspired strategy to combat the drug-resistant tumors by fabricating multiarm PEG-gated large pore-sized mesoporous silica nanoparticles for the Bcl-2-functional-converting peptide (denoted as N9@M-CA∼8P) payload and controlled release and realizing synergistic effects with celastrol integration at a low dosage as a curative sensitizer. Our results demonstrated that the N9 peptide could be pH-responsively released from the macropores of the M-CA∼8P nanosystem both in simulated physiological environments and in cancer cells and at tumor sites. Biosafe and enhanced therapeutic outcomes (90% tumor inhibition) were obtained by combination of the N9@M-CA∼8P nanosystem with celastrol coordinatively inducing mitochondrion-mediated cell apoptosis in resistant cancer cell lines and in the corresponding xenografted mice models. Overall, this study provides convincing evidence for effective and safe resistant cancer treatment through a stimulus-responsive biomacromolecule nanosystem combined with a low dosage of a natural compound.

Structural Regulation at Poly(ethylene glycol) Termini Facilitates the Formation of Injectable Hydrogels with Modulated Degradation and Release of Biomacromolecules

Hydrogels possessing modulated degradation and release behaviors are beneficial for the biological field. However, modulating the degradability and release behavior of a particular class of hydrogels requires a major structural alteration of a cross-linker as well as an adjustment in concentration, both of which affect the initial modulus and gelation kinetics. Herein, we address this shortcoming by a single step installation of a leaving nucleophile at the termini of PEG via the ether (O–CH2–Ph–, Cl′-PEG-Cl′) and ester (−Ph–COO–, Cl-PEG-Cl) spacers separately. These two PEG derivatives separately or in combination lead to the rapid formation of hydrogels when combined with a variety of macromolecules with tertiary amine functional group. The hydrogels exhibit a wide variation in degradation properties and time-dependent water swelling depending on the type and proportion of the PEG derivatives. The gelation kinetics is faster when the termini of the PEG derivative contain benzyl chloride groups connected through the ether spacer and is explained by density functional theory. Importantly, the ultimate moduli of the as prepared hydrogels are almost similar irrespective of the termini structure of the PEG derivatives and their proportion. The hydrogels exhibit modulated release profiles of model dextran and bovine serum albumin at pH 7.4. Prolonged delivery of biomacromolecules is achieved with the hydrogel prepared with Cl′-PEG-Cl′ or the combination Cl′-PEG-Cl′+Cl-PEG-Cl. More importantly, hydrogels prepared with Cl′-PEG-Cl′ or the Cl′-PEG-Cl′+Cl-PEG-Cl combination exhibit triggered release (60–100%) of a model protein (isoelectric point ≤ 7.4) and high molecular weight dextran (neutral) at a constant pH of 5 when compared to that at pH 7.4. The key advantages of our design are the access to a library of biological relevant hydrogels from easily available/synthesized amine-functional macromolecules and PEG derivatives with slight variations in the termini structures.

Raddeanin A synergistically enhances the anti-tumor effect of MAP30 in multiple ways, more than promoting endosomal escape

Biomacromolecules such as proteins and nucleic acids are very attractive due to their high efficiency and specificity as cancer therapeutics. In fact, the endocytosed macromolecules are often trapped in the endosomes and cannot exhibit pharmacological effects well. Many strategies have been used to address this bottleneck, and one promising approach is to exploit the endosomal escape-promoting effect of triterpenoid saponins to aid in the release of biomacromolecules. Here, Raddeanin A (RA, an oleanane-type triterpenoid saponin) was proved to significantly promote endosomal escape as it recruited Galectin-9, an endosomal escape event reporter. As expected, RA effectively enhanced the anti-tumor effect of MAP30 (a type I ribosome-inactivating protein derived from Momordica charantia). However, based on the results of fluorescent colocalization, RA did not significantly promote MAP30 release from endosomes, suggesting that RA enhances MAP30 activity not only by promoting endosomal escape. Furthermore, it was found that the inhibitors of micropinocytosis and caveolae could almost completely inhibit the cytotoxicity of MAP30 combined with RA without affecting the cytotoxicity of MAP30 alone, indicating that RA may regulate the endocytic pathway of MAP30. Meanwhile, the effect of RA is related to the intra vesicular pH and cholesterol content on cell membrane, and is also cell-type dependent. Therefore, RA enhanced the anti-tumor effect of MAP30 in multiple ways, not just by promoting endosomal escape. Our findings will help to further decipher the possible mechanisms by which triterpenoid saponins enhance drug activity, and provide a new perspective for improving the activity of endocytosed drugs.

Redox-Responsive Hydrogels for Tunable and "On-Demand" Release of Biomacromolecules.

In recent years, stimuli-responsive degradation has emerged as a desirable design criterion for functional hydrogels to tune the release of encapsulated payload as well as ensure degradation of the gel upon completion of its function. Herein, redox-responsive hydrogels with a well-defined network structure were obtained using a highly efficient thiol-disulfide exchange reaction. In particular, gelation occurred upon combining thiol-terminated tetra-arm polyethylene glycol (PEG) polymers with linear telechelic PEG-based polymers containing pyridyl disulfide units at their chain ends. Rapid gelation proceeds with good conversions (>85%) to yield macroporous hydrogels possessing high water uptake. Furthermore, due to the presence of the disulfide linkages, the thus-obtained hydrogels can self-heal. The obtained hydrogels undergo complete degradation when exposed to environments rich in thiol-containing agents such as dithiothreitol (DTT) and L-glutathione (GSH). Also, the release profile of encapsulated protein, namely, bovine serum albumin, can be tuned by varying the molecular weight of the polymeric precursors. Additionally, it was demonstrated that complete dissolution of the hydrogel to rapidly release the encapsulated protein occurs upon treating these hydrogels with DTT. Cytotoxicity evaluation of the hydrogels and their degradation products indicated the benign nature of these hydrogels. Additionally, the cytocompatible nature of these materials was also evident from a live/dead cell viability assay. One can envision that the facile fabrication and their ability to degrade on-demand and release their payload will make these benign polymeric scaffolds attractive for various biomedical applications.

Fabrication of Fe3O4/O‐Carboxylmethyl Chitosan Magnetic Particle Assembles in Inverse Miniemulsions for Loading and Release of Bovine Serum Albumin

AbstractFe3O4/O‐carboxylmethyl chitosan (OCMC) magnetic particle assembles (MPAs) with high magnetite loading and superparamagnetism were controllably prepared through Schiff base crosslinking reaction of OCMC‐stabilized Fe3O4 magnetic nanoparticles (OCMC‐Fe3O4 MNPs) in the dispersed phase of inverse miniemulsions. The Fe3O4/OCMC MPAs were composed of many tiny Fe3O4 MNPs, and they did not only inherit the good superparamagnetism of OCMC‐Fe3O4 MNPs, but also displayed high collective magnetic response to an external magnetic field. The crosslinked network of OCMC offered a good structural integrity of the Fe3O4/OCMC MPAs either in inverse emulsions or in aqueous dispersions within a wide pH range. The Fe3O4/OCMC MPAs displayed a reversible pH‐dependent loading and release behavior of a model protein, bovine serum albumin, exhibiting a great potential in functioning as nanocarriers for loading and release of biomacromolecules.

Magnetically triggered release of biologics

ABSTRACTThe development of platforms for the controlled release of therapeutic molecules remains a crucial research focus, as controlled release reduces the frequency of administration, minimizes side effects and improves compliance. However, biological conditions and diseases with a progression that exhibits strong temporal dependence, or those that can result in the evolution of tolerance to the therapeutic during continuous exposure, require the development of sophisticated release systems tailored to the needs to the individual and the disease. Thus, there has been emphasis on the development of platforms with remotely controlled release mechanisms. Specifically, magnetically triggered release utilizes magnetic nanoparticles as the remote control modality. Many reviews discuss the magnetically triggered release of small molecule drugs, however, the release of biomacromolecules has not been reviewed. This review examines the limited work on the magnetically triggered release of biomacromolecules and the challenges associated with their delivery. Important material parameters that have been used in this pursuit are discussed.

Starch Phosphate Microgels for Controlled Release of Biomacromolecules

Gel-forming starch phosphates with a content of acidic phosphate groups ranging from 2.1 to 3.8 mmol/g were obtained in a phosphoric acid-urea system. The rates of starch phosphate degradation in buffer solution in the absence of amylase and in the presence of this enzyme were investigated in vitro. Starch phosphate gels were shown to be prone to enzymatic degradation. However, the rate of biodegradation decreased gradually as the content of phosphate groups increased. The use of microgels with average particle sizes in the range of 7.8–60.1 μm for the production of controlled-release preparations of interferon-alpha 2b has been demonstrated to be possible in principle.

Surfactant-Modified Ultrafine Gold Nanoparticles with Magnetic Responsiveness for Reversible Convergence and Release of Biomacromolecules.

It is difficult to synthesize magnetic gold nanoparticles (AuNPs) with ultrafine sizes (<2 nm) based on a conventional method via coating AuNPs using magnetic particles, compounds, or ions. Here, magnetic cationic surfactants C16H33N+(CH3)3[CeCl3Br]- (CTACe) and C16H33N+(CH3)3[GdCl3Br]- (CTAGd) are prepared by a one-step coordination reaction, i.e., C16H33N+(CH3)3Br- (CTABr) + CeCl3 or GdCl3 → CTACe or CTAGd. A simple strategy for fabricate ultrafine (<2 nm) magnetic gold nanoparticles (AuNPs) via surface modification with weak oxidizing paramagnetic cationic surfactants, CTACe or CTAGd, is developed. The resulting AuNPs can highly concentrate the charges of cationic surfactants on their surfaces, thereby presenting strong electrostatic interaction with negatively charged biomacromolecules, DNA, and proteins. As a consequence, they can converge DNA and proteins over 90% at a lower dosage than magnetic surfactants or existing magnetic AuNPs. The surface modification with these cationic surfactants endows AuNPs with strong magnetism, which allows them to magnetize and migrate the attached biomacromolecules with a much higher efficiency. The native conformation of DNA and proteins can be protected during the migration. Besides, the captured DNA and proteins could be released after adding sufficient inorganic salts such as at cNaBr = 50 mmol·L-1. Our results could offer new guidance for a diverse range of systems including gene delivery, DNA transfection, and protein delivery and separation.

Microgels of Starch Phosphates for the Controlled Release of Biomacromolecules

Hydrogels on the basis of starch phosphates containing 2.1-3.8 mmol/g of phosphoric acid groups have been prepared by etherification of starch in an orthophosphoric acid-urea system. In in vitro experiments, the rate of starch phosphates degradation in a phosphate buffer in the absence and presence of а-amylase in the reaction mixture was studied. It was shown that phosphate starch is available for enzymatic hydrolysis; however, the rate of biodegradation was gradually reduced with increasing amounts of phosphate groups. The possibility of using microgels with average sizes 7.8-60.1 μm to create systems with interferon alpha-2b controlled release was demonstrated.

Chemical Modifications of Silicon Surfaces for the Generation of a Tunable Surface Isoelectric Point

The aim of this work was to generate a tunable surface isoelectric point (sIEP), where the surface is modified with two molecules: a weak base (pyridine), carrying a pH dependent positive charge, and a derivative of a strong acid (sulfate), carrying a permanent negative charge in a physiologically relevant pH range. To this end, silicon surfaces were modified with 3-aminopropyltriethoxysilane. These amine-modified surfaces were subsequently derivatized into pyridine- or sulfate-modified surfaces. Then, the surface pKa of pyridine-modified surfaces was determined by a fluorescent nanoparticle adhesion assay (FNAA). Next, these values were used to calculate in which ratio the chemicals must be present in the reaction mixture to generate a mixed pyridine/sulfate-modified surface with a target sIEP. After preparing surfaces with a target sIEP, an FNAA with positively and negatively charged nanoparticles was used to verify the sIEP of the generated surfaces. The FNAA revealed that pyridine-modified surfaces had a pKa of 6.69 ± 0.18. When an sIEP was generated, negative nanoparticles bound to surfaces at pH values below the sIEP and positive nanoparticles bound at pH values above the sIEP. Furthermore, we found sIEP values of 5.97 ± 0.88 when we aimed for an sIEP of 6.2, and 7.12 ± 0.21 when we aimed for an sIEP of 7.1. Finally, the pH dependent binding and release of a negatively and positively charged (bio)polymer was investigated for a target sIEP of 7. A negatively charged polymer (poly(I:C)) was bound at a pH < sIEP and released at a pH > sIEP with a release efficiency of 85 ± 9% and a positively charged polymer (trimethyl chitosan) bound at a pH > sIEP and released at a pH < sIEP with a release efficiency of 72 ± 9%. In conclusion, we established a method for preparing modified silicon surfaces with a tunable sIEP, which can be used for pH-dependent binding and release of biomacromolecules.

A novel sol–gel strategy to prepare temperature-sensitive hydrogel for encapsulation of protein

A novel sol–gel strategy was proposed to prepare temperature-sensitive hydrogel including the copolymerization of N-isopropylacrylamide and 3-methacryloxypropyl-trimethoxy silane and then the hydrolysis and condensation of the linear polymers through the sol–gel process under extra-mild conditions. Bovine serum albumin, as a model protein, was loaded into the hydrogel matrix to investigate the encapsulation and release properties. Experimental results indicated that the preparation conditions were valuable for the loading and release of biomacromolecules.