OATP-Targeted NIR Dye-Drug Conjugates for Cancer Imaging
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Solution Overview
Problem
Current methods lack effective molecular imaging and therapy for detecting and eradicating cancer metastasis, particularly in tumors and disseminated tumors, with no specific targeting mechanism for cancer cells over normal cells.
Innovation Solution
Development of near-infrared (NIR) cyanine-containing dyes chemically conjugated with therapeutic drugs, utilizing organic anion transporting peptides (OATPs) for targeted uptake and retention in cancer cells, enabling dual cancer imaging and therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cancer therapy methods are used, then cancer treatment is provided, but there is no specific targeting mechanism for cancer cells over normal cells, resulting in high toxicity and side effects
Solution Approach 1:
The patent applies local quality by designing dye-drug conjugates with specific molecular structures that selectively interact with OATP proteins expressed on cancer cell membranes. The conjugates incorporate cancer-targeting moieties (such as cyanine dyes) that bind preferentially to OATP proteins, delivering therapeutic drugs specifically to cancer cells while sparing normal cells, thus reducing toxicity while maintaining efficacy
Solution Approach 2:
The patent uses OATP proteins as intermediary carriers to facilitate targeted drug delivery. The OATP proteins serve as mediators that recognize and transport the dye-drug conjugates into cancer cells through their membrane transport function. This intermediary mechanism enables selective accumulation of therapeutic agents in cancer cells, achieving both targeting and reduced off-target effects
2Measurement precision
If molecular imaging methods are used for cancer detection, then tumor imaging is provided, but there is no effective molecular imaging method to detect tumor and metastases with specific targeting
Solution Approach 1:
The patent achieves multi-functionality by designing dye-drug conjugates that simultaneously serve as imaging agents and therapeutic drugs. The cyanine-containing dyes provide optical properties for fluorescence imaging, while the conjugated therapeutic agents provide cancer-killing activity. This single conjugate system enables both detection and treatment functions, addressing the need for targeted imaging and therapy
Solution Approach 2:
The patent utilizes the optical properties of cyanine dyes, which exhibit characteristic color changes and fluorescence emission in the near-infrared region. These color/optical changes enable the dyes to serve as imaging probes that can be detected by fluorescence microscopy or optical imaging systems, providing visual confirmation of cancer cell uptake and distribution
3Productivity
If non-specific drug delivery is used, then cancer therapy is provided, but there is no selective accumulation in cancer cells, resulting in poor therapeutic index
Solution Approach 1:
The patent applies segmentation by dividing the therapeutic agent into a conjugate system consisting of separate functional components: the dye moiety for targeting and imaging, the linker for stability, and the therapeutic drug for cancer treatment. This segmented design allows each component to be optimized for its specific function while working together to achieve selective accumulation and enhanced therapeutic index
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
The NIR dye-drug conjugates effectively target and accumulate in various cancer types, reducing drug toxicity and enhancing therapeutic efficacy against prostate, pancreatic, and brain tumors, while minimizing side effects on normal cells.
Implementation Method 1
The specificity of this class of NIR dye-drug conjugates for cancer but not normal cells is based upon the overexpression of membrane carrier proteins, organic anion transporting peptides (OATPs), in cancer, as compared with normal cells. The OATPs-mediated transporting mechanism
Implementation Method 2
NIR dye-drug conjugates are known to interact with nucleic acids and proteins noncovalently, and, therefore, once the NIR dye-drug conjugates enter into cancer cells, they are trapped in the mitochondrial and lysosomal compartments of the cancer cells
Implementation Method 3
Because the function of OATPs in cells is energy-dependent as carriers for drugs, metabolites and hormones, the uptake and retention of the NIR dye-drug conjugates by OATPs in cancer cells are also energy-dependent and occur only in live cells
Data Source
AI summary
A dye-drug conjugate for preventing, treating, or imaging cancer having the following structure:wherein R1 and R2 are independently selected from the group consisting of —H, alkyl, alkyl-sulphonate, alkylcarboxylic, alkylamino, aryl, —SO3H, —PO3H, —OH, —NH2, and -halogen; wherein Y1 and Y2 is independently selected from the group consisting of alkyl, aryl, aralkyl, alkylsulphonate, alkylcarboxylic, alkylamino, ω-alkylaminium, ω-alkynyl, PEGyl, PEGylcarboxylate, ω-PEGylaminium, ω-acyl-NH, ω-acyl-lysinyl-, ω-acyl-triazole, ω-PEGylcarboxyl-NH—, ω-PEGylcarboxyl-lysinyl, and ω-PEGylcarboxyl-triazole; wherein X is selected from the group consisting of a hydrogen, halogen, CN, Me, NH2, SH and OH; and R3 and R4 are independently a hydrogen, a therapeutic agent, or an imaging moiety, wherein the therapeutic agent is selected from the group consisting of a platinum-based therapeutic agent, a small molecule therapeutic agent, a peptide, a protein, a polymer, an siRNA, a microRNA, and a nanoparticle, wherein the imaging is a radio-isotope selected from the group consisting of F18, I-125, I-124 I-123, I-131, and small molecule labeled with any of these isotopes, or wherein the imaging moiety is a chelator-complexed radioactive isotope, wherein the radioactive isotope is selected from the group consisting of Cu-64, In-111, Tc-99m, Ga-68, Lu-177, Zo-89, Th-227 and Gd-157.