Development of therapeutic polyesters based on natural bioactive hydroxy acids

We proposed the idea of selecting hydroxy acids with clear chemical structures from natural Chinese herbal medicine extracts to prepare therapeutic polyesters, aiming to break through the limitation that current polyester drug carriers have no therapeutic function. By using the polycondensation reaction of bioactive hydroxy acid monomers widely present in Chinese herbal medicine plants, we have successfully prepared a series of polyester drug carrier materials with therapeutic functions (Figure 1), which have both good biological safety and high drug loading and drug release efficiency, it breaks through the major limitations of existing drug carriers that have no therapeutic effect, and is expected to promote major progress in Chinese herbal medicine-based biomaterials and tumor therapy.

Typical research outcomes:

1. 1) Ferulic Acid-Based Therapeutic Polyesters as Drug Carriers

For the first time, we used ferulic acid (a bioactive small molecule widely present in traditional Chinese medicines such as Ferulicum, Angelica, Chuanxiong) as a hydroxy acid monomer, and polymerized it into poly(ferulic acid) through polycondensation reaction. The prepared poly(ferulic acid) can be self-assembled into safe and non-toxic nanoparticles, which can be used as an excellent drug carrier to load a variety of insoluble small molecule anticancer drugs, and can effectively target and deliver drugs to tumor sites. At the same time, the polymer carrier itself is also can effectively inhibit tumors (Figure 2). This work realizes the concept of Chinese herbal medicine polymer for the first time, and the carrier itself has additional anti-tumor effect, achieving the effect that the carrier material is also a medicine, which provides a new idea for the research and development of Chinese herbal medicine-based biomaterials. (Adv. Funct. Mater., 2019, 1808646)

1. 2) Ursolic Acid-Based Therapeutic Polyesters as Drug Carrier

Based on the research outcomes of poly(ferulic acid), we further synthesized poly(ursolic acid) by polycondensation method using ursolic acid (a natural active ingredient widely distributed in Chinese herbal medicines such as Prunella vulgaris and Iron Holly) as the repeating structural unit. Poly(ursolic acid) can be self-assembled into nanocarrier particles, which can be loaded with drugs to deliver drugs, and has significant therapeutic effects on a variety of tumors. At the same time, poly(ursolic acid) carrier particles themselves also show additional tumor therapeutic effects (Figure 3). (Adv. Funct. Mater., 2020, 1907857)

1. 3) Salicylic acid-based therapeutic polyesters as drug carriers.

Salicylic acid is the functional active ingredient of the famous drug aspirin. We prepared poly(salicylic acid) by polycondensation reaction using salicylic acid as a monomer, and then self-assembled into nanocarriers for drug delivery (Figure 4). The poly(salicylic acid) nanocarriers can efficiently target and deliver drugs, enrich the drugs to the tumor site, and the poly(salicylic acid) nanocarriers can also significantly inhibit tumor growth. Therefore, this system has successfully expanded the therapeutic polyester system from the traditional Chinese herbal medicine system to the integrated Chinese and Western medicine system, which further provides ideas for the research and development of therapeutic biomaterials. （Adv. Funct. Mater., 2021, 2100805）

Amino acid-based therapeutic biomaterials

Wu Jun research group has developed a series of natural amino acid-based polymers and systematically explored the structure-effect relationship of these polymers as controlled-release drug carriers. These biomaterials have overcome the limitations of most current drug delivery carriers in terms of high drug-loading capacity and controllable delivery and release, laying the foundation for the development of new controlled-release drug delivery carriers. They can regulate their own metabolic pathways to treat a variety of diseases and efficiently load, target, and release drugs, achieving safe and effective treatment.

Typical research outcomes

1. 1) L-phenylalanine/ leucine-based drug deliver system

Hydrophobic L-phenylalanine polymer (Phe-PEA) prepared by condensation reaction can be used as a delivery platform for poorly soluble small-molecule drugs. After self-assembling into nanosized drug carriers, this phenylalanine polymer can effectively load a variety of poorly soluble small-molecule drugs (Figure 1). Wu Jun research group found that when Phe-PEA nanocarriers were loaded with daunorubicin, they could efficiently target bone marrow and leukemia cells in the treatment of acute lymphoblastic leukemia, delivering and releasing drugs while the carrier itself could relieve immune suppression through metabolic pathways and reactivate immune cells, inhibiting leukemia and achieving a self-therapeutic effect. This study is the first to use amino acid polymers to regulate metabolism for disease treatment (Adv. Sci., 2022, 2104134). Based on this research, the applicant further discovered that leucine polymer carriers could activate the mTOR signaling pathway to inhibit cell autophagy and enhance the killing effect of chemotherapy drugs on drug-resistant leukemia stem cells. Leucine polymer nanoparticles loaded with the chemotherapy drug daunorubicin can effectively eliminate drug-resistant leukemia cells and may become a new type of leukemia treatment drug that targets cellular metabolism (Haematologica, 2022, 107, 2344-2355).

1. 2) L-cysteine-based polydisulfide amide (Cys-PDSA) polymers

To achieve controlled drug release, the Wu group synthesized L-cysteine ester and fatty acid or derivatives via condensation reaction to prepare a library of reducible L-cysteine-based polydisulfide amide (Cys-PDSA) polymers. This class of polymers can self-assemble into nanocarriers with high drug loading capacity and exhibit specific responses to glutathione (GSH) and other substances in the tumor microenvironment, leading to rapid drug release, significantly improving tumor targeting and therapeutic efficacy while reducing toxic side effects (Figure 2). This drug delivery platform can achieve high loading and rapid release of platinum drugs and can also be consumed and cleared by GSH-induced consumption through disulfide bonds, reversing tumor cell resistance to platinum drugs and reducing their serious side effects (Nano Lett., 2018, 18, 4618-4625). In addition, for drug-resistant osteosarcoma with stem cell characteristics, this drug delivery platform can co-deliver the insoluble small molecule inhibitors Apatinib and GSK-J4, delivering drugs to the tumor microenvironment, inducing rapid release of small molecule drugs through GSH, and inducing endoplasmic reticulum apoptosis by the carrier itself, achieving a synergistic enhanced therapeutic effect on osteosarcoma with stemness. This system can greatly promote the efficacy of combination drug therapy, providing new ideas for the treatment of stemness-related tumors (Signal Transduct. Target. Ther., 2020, 5(1), 196). Furthermore, in the latest work, the Wu group found that cysteine polymers can not only clear GSH, but also inhibit GPX4. This drug delivery platform selectively induces ferroptosis in leukemia stem cells while delivering paclitaxel, effectively improving paclitaxel-induced bone marrow suppression and other toxic side effects while preserving normal hematopoietic stem cells, achieving an enhanced treatment for acute myeloid leukemia (ACS Nano, 2023, 17, 4, 3334–3345).

1. 3) Poly(mephalan) drug delivery system

The Wu group also synthesized and prepared poly(mephalan) by a one-step synthesis of the clinical amino acid-structured drug melphalan. The poly(melphalan) nanoparticles can effectively inhibit cell proliferation and induce cell apoptosis, exhibiting better tumor accumulation and anti-tumor effects than clinical melphalan formulations (Figure 3). This system represents a new peptide synthesis strategy and nanoplatform (Nano Today, 2021, 37, 101098).

Therapeutic biomaterials derived from food and medicine

Utilizing the concept of homology of medicine and food and low-carbon strategy, the food is used directly or after simple processing, combined with 3D scaffold material technology, the new biomaterial constructed can promote the regeneration of tissues and organs.
The traditional tofu preparation process was simply improved and used in the development of tofu scaffolds, which effectively avoided the introduction of toxic reagents and greatly improved the biological safety of scaffold materials. Ultimately, it has a good promoting effect on early osteogenesis, bone regeneration and the release of immune factors. (ACS Biomater. Sci. Eng. 2020, 6, 5, 3037–3045)