Alpha Polyglutamated Antifolates via Liposomal Delivery
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Solution Overview
Problem
Current antifolate therapies for cancer and other diseases face challenges such as lack of tumor selectivity and the development of drug resistance, leading to dose-limiting toxicities and reduced efficacy.
Innovation Solution
The development of alpha polyglutamated Antifolate compositions, which are designed to deliver higher-level polyglutamate forms of antifolates directly into cells using liposomes, thereby bypassing the need for intracellular conversion by FPGS and minimizing exposure to normal tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If conventional antifolate therapy is administered, then antifolate is transported into cells by RFC system, but dose-limiting toxicity occurs due to lack of tumor selectivity and effect on rapidly dividing normal cells
Solution Approach 1:
The patent segments the antifolate delivery system into extracellular polyglutamate formation (using FPGS in the extracellular environment or on cell surface) and intracellular transport. This allows the toxic antifolate to be generated outside cells or on surfaces, delivering it selectively to target cells while minimizing exposure to normal tissues. The segmentation separates the harmful effect from systemic circulation.
Solution Approach 2:
The patent uses FPGS (folylpoly-gamma-glutamate synthetase) as an intermediary enzyme that converts antifolate to polyglutamate form in the extracellular environment or on cell surfaces. This intermediary mechanism enables selective delivery of the activated toxic form to target cells through folate receptor-mediated endocytosis, while normal cells lacking the intermediary or with different receptor expression are spared.
2Reliability
If higher-level polyglutamate forms of antifolate are used, then cytotoxic effect on cancer cells is enhanced, but drug resistance develops through increased efflux pump activity and decreased transport
Solution Approach 1:
The patent applies preliminary action by forming polyglutamate forms of antifolate in the extracellular environment or on cell surfaces before the antifolate enters the cell. This pre-activation ensures that the highly cytotoxic polyglutamate form is delivered directly to the target cell interior via endocytosis, bypassing intracellular conversion steps that could be blocked by resistance mechanisms like efflux pumps.
Solution Approach 2:
The patent replaces the intracellular enzymatic conversion mechanism (FPGS inside the cell) with an extracellular or surface-based mechanism. This substitution eliminates the vulnerability to intracellular resistance mechanisms such as efflux pumps that pump out monoglutamate forms, while still achieving the same cytotoxic effect through extracellular polyglutamate formation and subsequent endocytic uptake.
3Ease of manufacture
If intracellular FPGS conversion is relied upon, then polyglutamate formation occurs inside the cell, but the process is vulnerable to resistance mechanisms and requires cellular machinery
Solution Approach 1:
The patent uses FPGS as an intermediary enzyme positioned in the extracellular environment or on cell surfaces rather than requiring intracellular FPGS. This intermediary approach enables polyglutamate formation outside the cell or at the cell membrane, eliminating dependence on intracellular cellular machinery and bypassing resistance mechanisms that target intracellular processes.
Solution Approach 2:
The patent substitutes the intracellular biochemical conversion system with an extracellular or surface-based system. This replacement removes the need for intracellular FPGS enzyme and associated cellular machinery, making the process more versatile and resistant to inhibition by cellular resistance mechanisms while maintaining polyglutamate formation capability.
Data Source
AI summary
The disclosure relates generally to alpha polyglutamated Antifolates, formulations containing liposomes filled with alpha polyglutamated Antifolates, methods of making the alpha polyglutamated Antifolates and liposome containing formulations, and methods of using polyglutamated alpha polyglutamated Antifolates and liposome containing formulations to treat hyperproliferative disorders (e.g., cancer) and disorders of the immune system (e.g., an autoimmune disease such as rheumatoid arthritis).