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Related Concept Videos

Prodrugs01:30

Prodrugs

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Prodrugs are a class of pharmaceutical compounds that undergo a biotransformation process within the body to be converted into a pharmacologically active drug. Prodrugs are designed to improve the therapeutic properties of the parent drug, such as enhancing bioavailability, increasing stability, or reducing toxicity. The concept of prodrugs revolves around modifying the chemical structure of the original drug to make it more effective or convenient for administration.
Prodrugs help overcome...
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Drug Biotransformation: Overview01:16

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Pharmaceutical substances known as xenobiotics are predominantly lipophilic and nonionized. This enables them to permeate lipid bilayers, such as cell membranes, and interact with intracellular target receptors. Lipophilic drugs have an advantage in crossing biological barriers and reaching their intended sites of action. However, lipophilic drugs often have a restricted capacity for renal expulsion or elimination from the body. When these drugs enter the kidneys and undergo glomerular...
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Targets for Drug Action: Overview01:26

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Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
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Carrier-Mediated Transport01:06

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Carrier-mediated transport is a pivotal process in drug absorption, particularly for lipid-insoluble drugs, and encompasses facilitated diffusion and active transport. Facilitated diffusion allows drugs to move along their concentration gradient without energy expenditure, while active transport utilizes ATP to drive drug movement against this gradient.
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Targeted Cancer Therapies02:57

Targeted Cancer Therapies

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The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
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Bioavailability Enhancement: Drug Stability Enhancement and GI Retention01:05

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Body:Improving a drug's stability in the gastrointestinal (GI) tract is paramount for enhancing its bioavailability and therapeutic effectiveness. Various strategies are employed to protect the drug from the harsh gastric milieu and to ensure its release and absorption at the desired site within the GI tract.Polymer coatings are one such method used to shield drugs from the stomach's acidic environment. By preventing premature drug release, these coatings improve the bioavailability of unstable...
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Related Experiment Video

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Targeted Plasma Membrane Delivery of a Hydrophobic Cargo Encapsulated in a Liquid Crystal Nanoparticle Carrier
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Hijacking Extracellular Targeted Protein Degrader-Drug Conjugates for Enhanced Drug Delivery.

Fangzhu Zhao1, Yan Wu1, Kaitlin Schaefer1

  • 1Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States.

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Degrader-drug conjugates (DDCs) enhance cancer treatment by combining antibody-drug conjugates and extracellular targeted protein degradation. DDCs improve lysosomal delivery and cytotoxicity, offering a next-generation therapeutic option.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • Antibody-based therapeutics are crucial for targeting tumor cells.
  • Antibody-drug conjugates (ADCs) and extracellular targeted protein degradation (eTPD) rely on lysosomal trafficking.
  • ADCs face limitations due to antigen internalization efficiency, while eTPD lacks cytotoxic potency.

Purpose of the Study:

  • To develop novel degrader-drug conjugates (DDCs) that overcome limitations of ADCs and eTPD.
  • To leverage eTPD's endocytic and recycling capabilities for enhanced lysosomal delivery.
  • To improve cytotoxic potency and broaden the utility of antibody therapeutics.

Main Methods:

  • Development of DDCs utilizing fast internalizing receptors: low-density lipoprotein receptor (LDLR) and chemokine receptor (CXCR7).
  • Assessment of lysosomal delivery efficiency and degradation of extracellular membrane proteins.
  • Evaluation of DDC cytotoxicity compared to conventional ADCs in vitro.

Main Results:

  • LDLR-based degraders demonstrated efficient and selective degradation of extracellular membrane proteins.
  • DDCs incorporating a cytotoxic payload exhibited enhanced cytotoxicity compared to conventional ADCs in vitro.
  • The dual modality of DDCs addresses internalization and potency challenges in current antibody therapeutics.

Conclusions:

  • DDCs represent a promising next-generation antibody therapeutic strategy.
  • This approach enhances lysosomal delivery and cytotoxic efficacy for cancer treatment.
  • DDCs offer broader utility and improved efficacy, expanding options for antibody-based therapies.