US-12616754-B2 - Composition for delivery of a bioactive agent and method of manufacture and use thereof

Abstract

Provided is a composition and method for delivery of bioactive agents to a cell or a subject. The composition includes nucleic acids derived from plants and the bioactive agents, and the nucleic acids are crossed linked by a cross-linking agent. Such composition is non-toxic, biocompatible and target specific. A method of making the composition is also provided.

Inventors

• Jeng-Shiung Jan
• Yu-Fon CHEN

Assignees

• NATIONAL CHENG KUNG UNIVERSITY

Dates

Publication Date

20260505

Application Date

20200714

Claims (18)

1. 1 . A composition comprising a plant-derived nucleic acid and a bioactive agent, wherein the plant-derived nucleic acid is crosslinked with a cross-linking agent.
2. 2 . The composition of claim 1 , wherein the plant-derived nucleic acid is derived from a soft part of a plant.
3. 3 . The composition of claim 2 , wherein the soft part of the plant is fruits, leaves, petals, flowers, roots, or stems of the plant.
4. 4 . The composition of claim 3 , wherein the nucleic acid is derived from a seed of the fruit of the plant.
5. 5 . The composition of claim 3 , wherein the fruit is kiwifruit, dragon fruit, pineapple, papaya, apple, lemon, orange, tangerine, tomato, mango, litchi, pear, date, passion fruit, banana, sweet potato, corn, or a combination thereof.
6. 6 . The composition of claim 1 , wherein the nucleic acid has a GC content greater than 40%.
7. 7 . The composition of claim 1 , wherein the cross-linking agent cross-links at least one of primary amines and hydroxyl groups of the nucleic acid.
8. 8 . The composition of claim 7 , wherein the cross-linking agent is genipin, 3,3′-dithiobis(sulfosuccinimidyl propionate), citric acid, transglutaminase, glutaraldehyde, 1,4-butanediol diglycidyl ether, carbodiimide, tannic acid, sulfonate, oxidized dextrins, hydrazide, alkoxyamine, ketone, periodic acid, calcium chloride, calcium carbonate, or a combination thereof.
9. 9 . The composition of claim 1 , which has a hydrodynamic diameter of from 50 nm to 5 μm.
10. 10 . The composition of claim 9 , wherein the hydrodynamic diameter is in a range of from 100 nm to 150 nm.
11. 11 . The composition of claim 1 , wherein the bioactive agent is hydrophobic.
12. 12 . The composition of claim 1 , wherein the bioactive agent is an anti-cancer drug, an anti-inflammatory drug, a small molecule compound drug, an anti-virus drug, a vaccine, or a combination thereof.
13. 13 . The composition of claim 12 , wherein the anti-cancer drug is a chemotherapy drug.
14. 14 . The composition of claim 13 , wherein the anti-cancer drug is doxorubicin, cisplatin, carboplatin, etoposide, vinorelbine, topotecan, irinotecan, gemcitabine, uracil-tegafur, vinorelbinen, docetaxel, paclitaxel, prednisone, pemetrexed, gefitinib, erlotinib, cetuximab, bevacizumab, or a combination thereof.
15. 15 . The composition of claim 12 , wherein the anti-virus drug is a nucleic acid analog.
16. 16 . The composition of claim 12 , wherein the anti-inflammatory drug is selected from the group consisting of zinc oxide, aspirin, ibuprofen, naproxen, meloxicam, celecoxib, and indomethacin.
17. 17 . The composition of claim 12 , wherein the vaccine is extracellular secreted protein A of enterohemorrhagic Escherichia coli , or hemagglutinin and neuraminidase of influenza virus.
18. 18 . A method of manufacturing the composition of claim 1 for delivery of the bioactive agent to a subject in need thereof, the method comprising: preparing an aqueous phase portion containing the plant-derived nucleic acid and the bioactive agent; preparing an oil phase portion containing a surfactant; mixing the aqueous phase portion and the oil phase portion to obtain an emulsified solution; sonicating the emulsified solution; and removing the oil phase portion so as to obtain the composition from the aqueous phase portion.

Description

BACKGROUND 1. Technical Field The present disclosure relates to compositions comprising nucleic acids as biomaterials to deliver bioactive agents, and more specifically to the use of naturally derived nucleic acids for drug delivery. The present disclosure also relates to methods of manufacture and use of the compositions comprising nucleic acids as drug delivery biomaterials. 2. Description of Related Art Cancers remain the major threats to human health. Among the various approach to treat cancer, chemotherapy is one of the most adopted treatment. Conventional chemotherapy causes cancer cells to stop growth and division by interfering with their DNA replication and cell mitosis. However, these agents are non-specific when being delivered into a subject for cancer treatment and could also harm healthy tissues, leading to unintended side effects. These side effects could be so severe that the damage made on healthy tissues has been related to a high mortality rate of cancer patients. Furthermore, the efficiency of delivering chemotherapeutic drugs to malignant tumors is relatively poor and requires high doses to be effective, further exacerbating damage of healthy tissues and inducing multidrug resistance. Therefore, the development of treatments that are specific toward cancer cells and have less side effects and higher therapeutic efficacy is of high priority in cancer treatment. In recent years, a range of bioavailable materials have emerged as candidates to improve therapeutic efficacies. These include polymeric nanoparticles, hydrogels, liposomes, and inorganic carriers that are designed to be activated under certain conditions. For example, the bioavailable material can be activated and release the active agent based on the characteristics of cancer cells such as pH differences, oxygen requirements, redox potentials, reactive oxygen species (ROS) and enzymes when being delivered into tumor's microenvironment. However, the availability of such biomaterials and cost-effectiveness of manufacture thereof into an adequate carrier for delivery of bioactive agents remain as the challenges in the field. For example, using DNA-origami to design nanocarriers has been a promising strategy for drug delivery, and nanostructures have been designed in rational geometries and precise spatial addressability, relying on the hydrogen bonding of complementary nitrogenous bases to maintain their structures. However, these approaches often lead to less than 100% yield of the desired product due to mis-assembly or mis-folding, and their preparation is often very expensive. Thus, a non-toxic and effective delivery of a bioactive agent is still in need for safe and efficient treatment of cancers and other diseases. SUMMARY Herein, the present disclosure is therefore provided with a composition and a method of manufacture thereof for delivering a bioactive agent to a subject in need thereof. In an aspect, the present disclosure provides a composition comprising a plant-derived nucleic acid and a bioactive agent, wherein the plant-derived nucleic acid is crosslinked with a cross-linking agent. In one embodiment, the composition comprises a plant-derived nucleic acid that is derived from a soft part of a plant, e.g., fruits, leaves, petals, flowers, roots or stems of a plant. In another embodiment, the nucleic acid is derived from a seed of the fruit of the plant. In a further embodiment, the fruit from which the nucleic acid is derived is kiwifruit, dragon fruit, pineapple, papaya, apple, lemon, orange, tangerine, tomato, mango, litchi, pear, date, passion fruit, banana, sweet potato, corn or a combination thereof. In an embodiment, the composition comprises a plant-derived nucleic acid with GC content greater than 40%. In another embodiment, the plant-derived nucleic acid has a GC content greater than 30%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, or 55%. In an embodiment, the composition comprising a plant-derived nucleic acid and a bioactive agent, wherein the plant-derived nucleic acid is crosslinked with a cross-linking agent that cross-links primary amines or hydroxyl groups of the nucleic acid. In another embodiment, the cross-linking agent is genipin, 3,3′-dithiobis (sulfosuccinimidyl propionate), citric acid, transglutaminase, glutaraldehyde, 1,4-butanediol diglycidyl ether, carbodiimide, tannic acid, sulfonate, oxidized dextrins, hydrazide, alkoxyamine, ketone, periodic acid, calcium chloride, calcium carbonate or a combination thereof. In an embodiment, the composition has a hydrodynamic diameter of from 50 nm to 5 μm. In another embodiment, the composition has a hydrodynamic diameter in a range of from 100 nm to 1 μm. In a further embodiment, the composition has a hydrodynamic diameter in a range of from 100 nm to 500 nm. In a further embodiment, the composition has a hydrodynamic diameter in a range of from 100 nm to 200 nm. In an even further embodiment, the composition has a h