ALA-Ester Conjugates for Tissue Penetration and Erythropoiesis
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Solution Overview
Problem
Current treatments for cancer and anemia, particularly those involving photodynamic therapy (PDT) and erythropoiesis, face limitations due to the hydrophilic nature of 5-aminolevulinic acid (ALA) and the toxicity and cost of erythropoietin (EPO), necessitating improved methods for enhanced penetration and reduced toxicity and cost.
Innovation Solution
Development of drug conjugates comprising 5-aminolevulinic acid (ALA), an aldehyde, and a carboxylic acid functioning as a histone deacetylase inhibitor (HDACI), which are designed to release active species in vivo for PDT-dependent and independent treatments, as well as for anemia treatment and erythropoiesis induction, with specific compounds like 1-(Octanoyloxy)ethyl-5-amino-4-oxopentanoate and 1-(Butyryloxy)butyl-5-amino-4-oxopentanoate.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Length of moving object
If ALA esters (methyl-ALA and hexyl-ALA) are used to improve penetrability, then lipophilicity is increased and tissue penetration is enhanced, but molecular complexity increases and metabolic stability may be reduced
Solution Approach 1:
The invention divides the single ester group in conventional ALA esters into two separate ester groups at different positions on the pyrrole ring. This segmentation allows each ester to be optimized independently for penetration and stability, resolving the contradiction between penetration enhancement and metabolic stability.
Solution Approach 2:
The patent creates composite ALA derivatives by combining two different ester groups (e.g., methyl and hexyl, or isopropyl and butyl) on the same molecule. This composite structure leverages the penetrability of lipophilic esters while the specific combination provides enhanced metabolic stability compared to single-ester structures.
2Productivity
If EPO is used for anemia treatment, then erythropoiesis is stimulated and hemoglobin levels increase, but treatment cost increases and thromboembolic risks are elevated
Solution Approach 1:
The patent uses ALA and its derivatives as intermediary compounds that stimulate erythropoiesis through a different mechanism than EPO. These compounds act as precursors in the heme synthesis pathway, indirectly promoting red blood cell production without the thromboembolic risks associated with direct EPO stimulation.
Solution Approach 2:
The invention employs small molecule ALA derivatives that are chemically synthesized and metabolized rapidly, replacing the need for expensive recombinant EPO proteins. These short-acting compounds provide cost-effective anemia treatment with favorable safety profiles.
3Object-affected harmful factors
If ALA is used for PDT therapy, then cancer cells are targeted and killed through singlet oxygen generation, but poor tissue penetration limits its effectiveness for deep tumors
Solution Approach 1:
The patent systematically varies the ester groups attached to the ALA core structure to optimize the balance between lipophilicity (for penetration) and water solubility (for cellular uptake). By changing parameters such as ester chain length and position, the compounds achieve enhanced tissue penetration while maintaining adequate solubility for effective PDT action.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These conjugates demonstrate enhanced antineoplastic activity under both PDT and non-PDT conditions with lower effects on normal cells, and induce erythropoiesis with improved hemoglobin production, potentially reducing the need for EPO and lowering treatment costs.
Implementation Method 1
ALA acyloxyalkyl ester prodrugs are hydrolyzed into ALA which induces PpIX synthesis
Implementation Method 2
Irradiation of ALA treated cancer cells in the presence of oxygen results in generation of singlet oxygen that is toxic to the tumor
Implementation Method 3
Pharmacological inhibition of histone deacetylase (HDAC) activity by small organic molecules (HDACIs)
Data Source
AI summary
The present invention provides drug conjugates comprising 5-aminolevulinic acid (ALA), an aldehyde and a carboxylic acid that may function as a histone deacetylase inhibitor (HDACI). These conjugates may serve as co-drugs which release a plurality of active species in vivo. The novel drug conjugates may be used, for the treatment or prevention of cancer in PDT-dependent and/or PDT-independent (nonPDT) treatments, as well as for cosmetic uses. In addition the present invention provides novel uses for both the novel and known compounds. According to some embodiments, the present invention provides drug conjugates (co-drugs) comprising (i) ALA, (ii) an aldehyde and (iii) a carboxylic acid that may function as a histone deacetylase inhibitor (HDACO for the treatment of anemia and/or for the induction of erythropoiesis.