Predictive Platforms of Bond Cleavage and Drug Release Kinetics for Macromolecule–Drug Conjugates

Macromolecule–drug conjugates (MDCs) occupy a critical niche in modern pharmaceuticals that deals with the assembly and combination of a macromolecular carrier, a drug cargo, and a linker toward the creation of effective therapeutics. Macromolecular carriers such as synthetic biocompatible polymers and proteins are often exploited for their inherent ability to improve drug circulation, prevent off-target drug cytotoxicity, and widen the therapeutic index of drugs. One of the most significant challenges in MDC design involves tuning their drug release kinetics to achieve high spatiotemporal precision. This level of control requires a thorough qualitative and quantitative understanding of the bond cleavage event. In this review, we highlight specific research findings that emphasize the importance of establishing a precise structure–function relationship for MDCs that can be used to predict their bond cleavage and drug release kinetic parameters. Expected final online publication date for the Annual Review of Chemical and Biomolecular Engineering, Volume 12 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Design and Synthesis of a Novel Gabapentin-Phosphotidylcholine Conjugate for Targeting to Phospholipase A2 Enzyme through Nanostructured Lipid Carrier

Current Computer - Aided Drug Design ◽

10.2174/1573409916666201224153414 ◽

2020 ◽

Vol 16 ◽

Author(s):

Anjali P.B ◽

Jawahar N. ◽

Jubie S. ◽

Neetu Yadav ◽

Selvaraj A. ◽

...

Keyword(s):

Drug Release ◽

Phospholipase A2 ◽

Release Kinetics ◽

Entrapment Efficiency ◽

Structural Analog ◽

Fickian Diffusion ◽

Release Kinetic ◽

Nanostructured Lipid Carrier ◽

Discovery Studio

Background: : Epilepsy is a genuine neurological turmoil that effects around 50 million individuals around the world. Practically 30% of epileptic patients experience the ill effects of pharmaco-obstruction, which is related with social seclusion, subordinate conduct, low marriage rates, joblessness, mental issues and diminished personal satisfaction. At present accessible antiepileptic drugs have a restricted viability, and their negative properties limit their utilization and cause challenges in patient administration. Gabapentin 1-(aminomethyl)cyclohexane acetic acid, Gbp , (trade name Neurontin), a structural analog of γ-aminobutyric acid (GABA), BCS class 3 drug with having permeability issues. Objective: This work was an attempt to formulate and characterize a new approach to treat epilepsy by targeting to Phospholipase A2 Enzyme through Nanostructured Lipid Carrier. Methods: Docking studied carried out using Accelrys Discovery studio 4.1 Client and gabapentin and phosphotidylcholine were conjugated through chemical conjugation. Nanostructured lipid carrier (NLC) was prepared using hot homogenization technique. Results: The libdock score of Gabapentin- Phosphotidylcholine conjugate (192.535) were found to be more than Gabapentin (77.1084) and Phosphotidylcholine (150.212). For the optimized formulation the particle size (50.08), zeta potential (-1.48), PDI (0.472) and entrapment efficiency (77.8) was observed. The NLC was studies for in-vitro drug release studies and release kinetics. Finally found that the drug release from the NLC followed Higuchi release kinetic and the mode of drug release from the NLC was found to be Non- Fickian diffusion. Conclusion: The formulated Nanostructured lipid carrier of Gabapentin-Phosphotidylcholine conjugate may be able to use to prevent seizure.

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Design, Synthesis and Studies on Novel Polymeric Prodrugs of Erlotinib for Colon Drug Delivery

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200811124013 ◽

2020 ◽

Vol 20 ◽

Author(s):

Sahil Kumar ◽

Bandna Sharma ◽

Tilak R. Bhardwaj ◽

Rajesh K. Singh

Keyword(s):

Drug Delivery ◽

Colon Cancer ◽

Drug Release ◽

Anticancer Agents ◽

Release Kinetics ◽

In Vitro Release ◽

Specific Treatment ◽

Drug Conjugates ◽

Polymer Drug Conjugates

Aims: In the present study, polymer-drug conjugates were synthesized based on azo-bond cleavage drug delivery approach for targeting erlotinib as anticancer drug specifically to the colon for the proficient treatment of colon cancer. Background: Colon cancer (CC) is the third commonly detected tumor worldwide and it make up about 10 % of all cases of cancers. Most of the chemotherapeutic drugs available for treating colon cancer are not only toxic to cancerous cells but also to the normal healthy cells. Among the various approaches to get rid of the adverse effects of anticancer agents, prodrugs are one of the most imperative approaches. Objective: The objective of the study is to chemically modify the erlotinib drug through azo-bond linkage and suitable spacer which will be finally linked to polymeric backbone to give desired polymer linked prodrug. The azo reductase enzyme present in colon is supposed to cleave the azo-bond specifically and augment the drug release at the colon. Methods: The synthesized conjugates were characterized by IR and 1H-NMR spectroscopy. The cleavage of aromatic azobond resulted in a potential colon-specific liberation of drug from conjugate studied in rat fecal contents. In vitro release profiles of polyphosphazene-linked conjugates of erlotinib have been studied at pH 1.2, pH 6.8 and pH 7.4. The stability study was designed to exhibit that free drug was released proficiently and unmodified from polyphosphazene-erlotinib conjugates having aromatic azo-bond in artificial colon conditions. Results: The synthesized conjugates were demonstrated to be stable in simulated upper gastro-intestinal tract conditions. The drug release kinetics shows that all the polymer-drug conjugates of erlotinib follow zero-order release kinetics which indicates that the drug release from the polymeric backbone is independent of its concentration. Kinetic study of conjugates with slope (n) shows the anomalous type of release with an exponent (n) > 0.89 indicating a super case II type of release. Conclusion: These studies indicate that polyphosphazene linked drug conjugates of erlotinib could be the promising candidates for the site-specific treatment of colon cancer with least detrimental side-effects.

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