PLGA Microparticles for Targeted PH Therapy
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Solution Overview
Problem
Pulmonary hypertension (PH) and its severe subtype pulmonary arterial hypertension (PAH) have inadequate treatment options, with high mortality rates despite current therapies, characterized by metabolic dysregulation, pro-proliferative states, and adverse pulmonary vascular remodeling and stiffness.
Innovation Solution
Therapeutic particles comprising a biocompatible polymer, such as poly(lactic-co-glycolic acid) (PLGA), encapsulating a YAP1/WWTR1 inhibiting agent like verteporfin and a glutaminase inhibiting agent like CB-839, designed for controlled release to target the pulmonary vascular compartment, addressing the molecular origins of PH by inhibiting key pathways involved in vascular cell proliferation and remodeling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current vasodilator drugs are used for treatment of pulmonary hypertension, then symptomatic relief is achieved, but mortality remains high and disease progression continues
Solution Approach 1:
The patent extracts and targets the specific molecular pathways (YAP1/WWTR1 and GLS1) that drive pulmonary vascular remodeling and metabolic dysregulation in PH, separating the disease-modifying target from the symptomatic treatment approach of conventional vasodilators
Solution Approach 2:
The patent employs preliminary action by using PLGA microparticles that are pre-loaded with verteporfin and CB-839, designed to release these agents in a controlled manner over time to prevent further vascular remodeling before it progresses to irreversible stages
2Quantity of substance
If systemic delivery of inhibitors is used, then broad coverage is achieved, but systemic side effects increase
Solution Approach 1:
The patent segments the drug delivery system into targeted microparticles that localize to the pulmonary vascular compartment, dividing the treatment effect from systemic circulation and concentrating the therapeutic action where it is needed most
Solution Approach 2:
The PLGA microparticles serve as an intermediary carrier that delivers the inhibitors specifically to the pulmonary vasculature, mediating between the administered drug and the target tissue while minimizing exposure of other organs
3Speed
If rapid release of inhibitors is used, then immediate therapeutic effect is achieved, but duration of action is insufficient for disease modification
Solution Approach 1:
The patent implements periodic action through the controlled release mechanism of PLGA microparticles, which release verteporfin and CB-839 in a sustained, periodic manner over days to weeks, maintaining therapeutic levels without requiring continuous dosing
Solution Approach 2:
The patent changes the release rate parameter of the drug delivery system by adjusting PLGA composition and structure, enabling the microparticles to release inhibitors at an optimized rate that balances immediate effect with prolonged duration of action
Data Source
AI summary
Disclosed are compositions comprising a YAP1/WWRT1 inhibiting agent and a glutaminase inhibiting agent and methods of their use. Disclosed herein are therapeutic particles comprising a biocompatible polymer, a YAP1/WWRT1 inhibiting agent, and a glutaminase inhibiting agent. In one aspect, disclosed herein are methods of treating a pulmonary disease in a subject in need of such treatment comprising administering the therapeutic particle to the subject.