scholarly journals pH-responsive antibodies for therapeutic applications

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Tomasz Klaus ◽  
Sameer Deshmukh
Keyword(s):  
Drug Delivery ◽  
Treatment Outcome ◽  
Tumor Microenvironment ◽  
Dependent Manner ◽  
Therapeutic Antibodies ◽  
Ph Responsive ◽  
Biologic Drugs ◽  
Car T ◽  
Ph Dependent ◽  
The Brain

AbstractTherapeutic antibodies are instrumental in improving the treatment outcome for certain disease conditions. However, to enhance their efficacy and specificity, many efforts are continuously made. One of the approaches that are increasingly explored in this field are pH-responsive antibodies capable of binding target antigens in a pH-dependent manner. We reviewed suitability and examples of these antibodies that are functionally modulated by the tumor microenvironment. Provided in this review is an update about antigens targeted by pH-responsive, sweeping, and recycling antibodies. Applicability of the pH-responsive antibodies in the engineering of chimeric antigen receptor T-cells (CAR-T) and in improving drug delivery to the brain by the enhanced crossing of the blood–brain barrier is also discussed. The pH-responsive antibodies possess strong treatment potential. They emerge as next-generation programmable engineered biologic drugs that are active only within the targeted biological space. Thus, they are valuable in targeting acidified tumor microenvironment because of improved spatial persistence and reduced on-target off-tumor toxicities. We predict that the programmable pH-dependent antibodies become powerful tools in therapies of cancer.

Glycan chip based on structure switchable DNA linker for on-chip biosynthesis of cancer-associated complex glycans

2021 ◽  
Author(s):  
Hye Ryoung Heo ◽  
Kye Il Joo ◽  
Jeong Hyun Seo ◽  
Chang Sup Kim ◽  
Hyung Joon Cha
Keyword(s):  
Breast Cancer Cells ◽  
Enzymatic Reactions ◽  
Dependent Manner ◽  
Ph Responsive ◽  
Quantitative Analyses ◽  
Ph Dependent ◽  
Complex Glycans ◽  
On Chip ◽  
Complex Glycan ◽  
Mcf 7

Abstract On-chip glycan biosynthesis is an effective strategy for preparing useful complex glycan sources and for preparing glycan-involved applications simultaneously. However, current methods have some limitations when analyzing biosynthesized glycans and optimizing enzymatic reactions, which could result in undefined glycan structures on a surface, leading to unequal and unreliable results. In this work, a novel glycan chip was developed by introducing a pH-responsive i-motif DNA linker to control the immobilization and isolation of glycans on chip surfaces in a pH-dependent manner. On-chip enzymatic glycosylations were optimized for uniform biosynthesis of cancer-associated Globo H hexasaccharide and its related complex glycans through stepwise quantitative analyses of isolated products from the surface. Successful interaction analyses of the anti-Globo H antibody and MCF-7 breast cancer cells with on-chip biosynthesized Globo H-related glycans demonstrated the feasibility of the structure-switchable DNA linker-based glycan chip platform for on-chip complex glycan biosynthesis and glycan-involved applications.

scholarly journals Effect of pH-Responsive Charge-Conversional Polymer Coating to Cationic Reduced Graphene Oxide Nanostructures for Tumor Microenvironment-Targeted Drug Delivery Systems

Nanomaterials ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 1289 ◽  
Author(s):  
Kitae Ryu ◽  
Jaehong Park ◽  
Tae-il Kim
Keyword(s):  
Drug Delivery ◽  
Tumor Microenvironment ◽  
Targeted Drug Delivery ◽  
Ph Responsive ◽  
Ethylene Imine ◽  
Serum Stability ◽  
Reduced Graphene ◽  
Targeted Drug ◽  
Poly Ethylene ◽  
Targeted Drug Delivery Systems

Tumor tissue represents a slightly acidic pH condition compared to normal tissue due to the accumulation of lactic acids via anaerobic metabolism. In this work, pH-responsive charge-conversional polymer (poly(ethylene imine)-poly(l-lysine)-poly(l-glutamic acid), PKE polymer) was employed for endowing charge-conversional property and serum stability to poly(ethylene imine) conjugated reduced graphene oxide-based drug delivery system (PEI-rGO). Zeta-potential value of PEI-rGO coated with PK5E7 polymer (PK5E7(PEI-rGO)) was −10.9 mV at pH 7.4 and converted to 29.2 mV at pH 6.0, showing pH-responsive charge-conversional property. Sharp-edged plate morphology of PEI-rGO was transformed to spherical nanostructures with vague edges by PK5E7 coating. Size of PK5E7(PEI-rGO) was found to be smaller than that of PEI-rGO in the serum condition, showing its increased serum stability. Loaded doxorubicin (DOX) in PK5E7(PEI-rGO) could be released rapidly in lysosomal condition (pH 5.0, 5 mM glutathione). Furthermore, DOX-loaded PK5E7(PEI-rGO) showed enhanced anticancer activity in HeLa and A549 cells in the tumor microenvironment-mimicking condition (pH 6.0, serum), which would be mediated by non-specific cellular interaction with decorated serum proteins. These results indicate that the pH-responsive charge-conversional PKE polymer coating strategy of cationic rGO nanostructures possesses a potential for acidic tumor microenvironment-targeted drug delivery systems.

scholarly journals Glycan chip based on structure-switchable DNA linker for on-chip biosynthesis of cancer-associated complex glycans

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hye Ryoung Heo ◽  
Kye Il Joo ◽  
Jeong Hyun Seo ◽  
Chang Sup Kim ◽  
Hyung Joon Cha
Keyword(s):  
Breast Cancer Cells ◽  
Enzymatic Reactions ◽  
Dependent Manner ◽  
Ph Responsive ◽  
Quantitative Analyses ◽  
Ph Dependent ◽  
Complex Glycans ◽  
On Chip ◽  
Complex Glycan ◽  
Mcf 7

AbstractOn-chip glycan biosynthesis is an effective strategy for preparing useful complex glycan sources and for preparing glycan-involved applications simultaneously. However, current methods have some limitations when analyzing biosynthesized glycans and optimizing enzymatic reactions, which could result in undefined glycan structures on a surface, leading to unequal and unreliable results. In this work, a glycan chip is developed by introducing a pH-responsive i-motif DNA linker to control the immobilization and isolation of glycans on chip surfaces in a pH-dependent manner. On-chip enzymatic glycosylations are optimized for uniform biosynthesis of cancer-associated Globo H hexasaccharide and its related complex glycans through stepwise quantitative analyses of isolated products from the surface. Successful interaction analyses of the anti-Globo H antibody and MCF-7 breast cancer cells with on-chip biosynthesized Globo H-related glycans demonstrate the feasibility of the structure-switchable DNA linker-based glycan chip platform for on-chip complex glycan biosynthesis and glycan-involved applications.

Daunorubicin -TiO2 Nanocomposites As ‘smart' pH-Responsive Drug Delivery System,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3479-3479 ◽  
Author(s):  
Hai-jun Zhang ◽  
Bao-An Chen
Keyword(s):  
Drug Delivery ◽  
Side Effects ◽  
Cancer Cells ◽  
Drug Delivery System ◽  
Delivery System ◽  
Human Leukemia ◽  
Dependent Manner ◽  
Ph Responsive ◽  
Tio2 Nps ◽  
Anti Tumor Activity

Abstract Abstract 3479 Daunorubicin (DNR) with a broad spectrum of anti-tumor activity is limited due to the serious side-effects in the clinical application. The aim of this study was to explore the novel pH-responsive drug delivery system (DDS) based on titanium dioxide (TiO2) nanoparticles (Nps) for its potential roles to enable more intelligently controlled release, enhance chemotherapeutic efficiency, and reduce the side-effects of DNR. DNR was loaded onto the TiO2 Nps by forming (six-membered chelate) complexes with transition metal Ti to contract DNR-TiO2 nanocomposites as DDS. The encapsulation efficiency and loading efficiency of DNR loaded TiO2 Nps were assessed and calculated as 65.46±6.82% and 20.63±3.55%, respectively.The DNR was released from the DDS much more rapidly at pH 5.0 and 6.0 than at pH 7.4. The release behavior is a desirable characteristic for tumor-targeted drug delivery. Most DNR will remain in the carrier for a considerable time period at normal physiological conditions (pH 7.4), indicating the potential for the prolonged DNR retention time in the blood circulation and thereby greatly reducing the side effects to the normal tissues. On the other hand, once the DNR loaded TiO2 Nps are taken up by tumor cells via endocytotic process, a faster release may occur at lower local pH, i.e, inside the endosome and lysosome of cancer cells ((pH 4.5∼6.5), leading to the significant improvement in cancer treatment efficacy. The DNR- TiO2 nanocomposites as DDS induced the remarkable improvement in the anti-tumor activity, which were demonstrated by the flow cytometry, MTT assay and nuclear DAPI staining. Furthermore, the possible signaling pathway was explored by Western blot. For instance, in human leukemia cells (K562 cells), our observations demonstrated that the DDS could obviously increase the intracellular concentration of DNR and enhance its potential anti-tumor efficiency through inducing apoptosis in a caspase-dependent manner, indicating that DNR-TiO2 nanocomposites could act as an efficient DDS importing DNR into target cancer cells. These findings revealed that such ‘smart' DNR delivery strategy represent a promising approach in hematologic malignancy therapy. Disclosures: No relevant conflicts of interest to declare.

Rationalizing the pH-Activity Response for Escherichia Coli’s Glycinamide Ribonucleotidetransformylase Through Computational Methods

2019 ◽  
Author(s):  
Adrian Roitberg ◽  
Pancham Lal Gupta
Keyword(s):  
Transfer Reaction ◽  
Catalytic Mechanism ◽  
Ph Dependence ◽  
Ph Effects ◽  
Dependent Manner ◽  
E Coli ◽  
Gar Tfase ◽  
Activity Curve ◽  
Ph Dependent ◽  
Formyl Transfer

<div>Human Glycinamide ribonucleotide transformylase (GAR Tfase), a regulatory enzyme in the de novo purine biosynthesis pathway, has been established as an anti-cancer target. GAR Tfase catalyzes the formyl transfer reaction from the folate cofactor to the GAR ligand. In the present work, we study E. coli GAR Tfase, which has high sequence similarity with the human GAR Tfase with most functional residues conserved. E. coli GAR Tfase exhibits structural changes and the binding of ligands that varies with pH which leads to change the rate of the formyl transfer reaction in a pH-dependent manner. Thus, the inclusion of pH becomes essential for the study of its catalytic mechanism. Experimentally, the pH-dependence of the kinetic parameter kcat is measured to evaluate the pH-range of enzymatic activity. However, insufficient information about residues governing the pH-effects on the catalytic activity leads to ambiguous assignments of the general acid and base catalysts and consequently its catalytic mechanism. In the present work, we use pH-replica exchange molecular dynamics (pH-REMD) simulations to study the effects of pH on E. coli GAR Tfase enzyme. We identify the titratable residues governing the pH-dependent conformational changes in the system. Furthermore, we filter out the protonation states which are essential in maintaining the structural integrity, keeping the ligands bound and assisting the catalysis. We reproduce the experimental pH-activity curve by computing the population of key protonation states. Moreover, we provide a detailed description of residues governing the acidic and basic limbs of the pH-activity curve.</div>

Nanostructures for pH-sensitive Drug Delivery and Magnetic Resonance Contrast Enhancement Systems

2018 ◽  
Vol 25 (25) ◽  
pp. 3036-3057 ◽  
Author(s):  
Xiao Sun ◽  
Guilong Zhang ◽  
Zhengyan Wu
Keyword(s):  
Drug Delivery ◽  
Magnetic Resonance ◽  
Drug Release ◽  
Contrast Enhancement ◽  
General Strategy ◽  
Ph Responsive ◽  
Physicochemical Changes ◽  
Magnetic Resonance Contrast ◽  
Resonance Contrast ◽  
Magnetic Resonance Contrast Enhancement

According to the differences of microenvironments between tumors and healthy tissues, if the anticancer drugs or magnetic resonance contrast agents (MRCAs) can be controlled to precisely match physiological needs at targeted tumor sites, it is expected to acquire better therapeutic efficacy and more accurate diagnosis. Over the decade, stimuli-responsive nanomaterials have been a research hotspot for cancer treatment and diagnosis because they show many excellent functions, such as in vivo imaging, combined targeting drug delivery and systemic controlled release, extended circulation time, etc. Among the various stimuli nanosystems, pH-stimuli mode is regarded as the most general strategy because of solid tumors acidosis. When exposed to weakly acidic tumor microenvironment, pH-responsive nanoplatforms can generate physicochemical changes for their structure and surface characteristics, causing drug release or contrast enhancement. In this review, we focused on the designs of various pH-responsive nanoplatforms and discussed the mechanisms of controlled drug release or switch on-off in MRCAs. This review also discussed the efficacy of cellular internalization for these nanoplatforms via endocytosis of acidic tumor cell. Meanwhile, nanoplatforms response to acidic intracellular pH (such as endosome, lysosome) are discussed, along with approaches for improving drug release performance and magnetic resonance contrast enhancement. A greater understanding of these pH-responsive nanoplatforms will help design more efficient nanomedicine to address the challenges encountered in conventional diagnosis and chemotherapy.

Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease

2020 ◽  
Vol 26 (37) ◽  
pp. 4721-4737 ◽  
Author(s):  
Bhumika Kumar ◽  
Mukesh Pandey ◽  
Faheem H. Pottoo ◽  
Faizana Fayaz ◽  
Anjali Sharma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Side Effects ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Neural Cells ◽  
Blood Brain ◽  
The Brain

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

Brain Drug Delivery: Overcoming the Blood-brain Barrier to Treat Tauopathies

2020 ◽  
Vol 26 (13) ◽  
pp. 1448-1465 ◽  
Author(s):  
Jozef Hanes ◽  
Eva Dobakova ◽  
Petra Majerova
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Neurodegenerative Disorders ◽  
Brain Barrier ◽  
Neuronal Function ◽  
Brain Drug Delivery ◽  
Naturally Occurring ◽  
Blood Brain ◽  
Traditional Approaches ◽  
The Brain

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.

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