Modification of living cells with microencapsulated drugs for use in regenerative medicine / Модификация живых клеток микроинкапсулированными лекарствами для использования в регенеративной медицине тема диссертации и автореферата по ВАК РФ 00.00.00, кандидат наук Шэнь Нинфей

• Шэнь Нинфей
• кандидат наук
• 2025

Оглавление диссертации кандидат наук Шэнь Нинфей

Contents

Summary

Publications

Introduction

Chapter 1. Literature review

1.1. Cell therapy

1.2. Non-genetic modification of cells for drug delivery

1.3. Exploiting cell-based systems for drug delivery

1.4. Therapeutic loading strategies

1.4.1. Attachment of nanoparticles to the cell surface

1.4.2. Intracellular encapsulation of nanoparticles

1.5. Application of living cells for regenerative medicine

1.6. Cytoprotective agents and proteins

Chapter 2. Materials and methods

2.1. Synthesis and characterization of PLGA/Prx1 microparticles and

PLGA/SBN nanoparticles

2.1.1. Synthesis of PLGA/Prx1 microparticles

2.1.2. Synthesis of PLGA/SBN nanoparticles

2.1.3. Characterization of PLGA/Prx1 microparticles and PLGA/SBN nanoparticles

2.2. Cell culture

2.3. Analysis of macrophage activation by Prx1 released from PLGA microparticles

2.4. PLGA/Prx1 microparticle conjugation to 3T3 cells

2.5. PLGA/SBN nanoparticle uptake by MSCs

2.6. Oxidative stress induction and measurement of cell viability

2.7. Cell viability analysis

2.8. Measurement of protein expression level

2.9. Analysis of 3T3 cell senescence

2.10. Scratch assay

2.11. In vivo study

2.12. Statistical analysis

Chapter 3. Results

3.1. Characterization of PLGA/Prx1 microformulations

3.2. Bioactivity of Prx1 released from PLGA/Prx1 microparticles

3.3. PLGA/Prx1 microparticle conjugation to 3T3 cells

3.4. Protective effects of PLGA/Prx1 microparticles under oxidative stress

3.5. Fibroblast modification with PLGA/Prx1 microparticles stimulates cell migration

3.6. Modification of fibroblasts with PLGA/Prx1 microparticles stimulates collagen type I production

3.7. Characterization of PLGA/SBN nanoformulations

3.8. Characterization of isolated MSCs

3.9. PLGA/SBN nanoparticles are rapidly internalized by MSCs

3.10. Treatment of MSCs with PLGA/SBN NPs upregulates antioxidant enzymes and enhances cell resistance to oxidative stress

3.11. Modification of MSCs with PLGA/SBN nanoparticles accelerates cutaneous wound closure

3.14 PLGA/SBN modification of MSCs leads to improved cell survival and cytokine expression alterations in the wound microenvironment

Chapter 4. Discussion

Conclusions

List of Abbreviations

Acknowledgements

References

Введение диссертации (часть автореферата) на тему «Modification of living cells with microencapsulated drugs for use in regenerative medicine / Модификация живых клеток микроинкапсулированными лекарствами для использования в регенеративной медицине»

Summary

Fibroblasts and mesenchymal stromal cells hold great promise for regenerative medicine. However, the therapeutic advantages have been diminished since transplanting fibroblasts and mesenchymal stromal cells (MSCs) into injured or inflamed tissues results in a poor survival rate. Innovative methods for altering cells with the goal of enhancing their characteristics and therapeutic effectiveness have been developed. It was hypothesized that the cells can be physically or chemically modified by artificial drug-loaded particles to provide them new therapeutic functionalities. In certain cases, non-genetic alteration of the cells may also be employed to modify their specialized roles, enhance their secretory capacity, and improve their capacity to migrate to target regions, altering their destiny. In this work, we aimed to develop two strategies for boosting the cell resistance to oxidative stress and enhancing their regenerative property. In particular, we proposed modification of the fibroblast surface by covalent attachment of microparticles based on polylactide-co-glycolide (PLGA) containing the protein peroxiredoxin-1 (Prx1) and modification of MSCs by internalization of PLGA nanoparticles containing a small-molecule agent silibinin (SBN). The results demonstrated that the released Prx1 interacts with TLR4 receptors on the fibroblast surface that increases cell survival under oxidative stress, cell motility, and production of collagen type I. In the case of PLGA/SBN-modified MSCs, the released SBN stimulates the Nrf2/Keap1 signaling pathway after internalization, which activates a number of genes involved in the production of antioxidant enzymes. In addition, SBN directly scavenges reactive oxygen species (ROS). As a consequence, after being treated with tert-butyl hydroperoxide (tBHP), PLGA/SBN-modified MSCs demonstrated higher viability. Modification of MSCs with silibinin-loaded PLGA nanoparticles increased their survival upon transplantation to the cutaneous wound and improved wound healing. Overall, our work implies that modifying living cells with synthetic cytoprotective materials could serve as a feasible method for enhancing cell survival after delivery and expanding their use in regenerative medicine.

Publications

1. Ningfei Shen, Xiaoli Qi, Dmitry V. Bagrov, Sergey P. Krechetov, Mars G. Sharapov,Mikhail O. Durymanov*, Surface modification of fibroblasts with peroxiredoxin-1-loaded polymeric microparticles increases cell mobility, resistance to oxidative stress and collagen I production, Colloids and Surfaces B: Biointerfaces, 2022, 219, 112834.

2. Marina V. Volkova, Ningfei Shen, Anna Polyanskaya, Xiaoli Qi, Valery V. Boyarintsev, Elena V. Kovaleva, Alexander V. Trofimenko, Gleb I. Filkov, Alexandre V. Mezentsev, Sergey P. Rybalkin, Mikhail O. Durymanov*, Tissue-oxygen-adaptation of bone marrow-derived mesenchymal stromal cells enhances their immunomodulatory and pro-angiogenic capacity, resulting in accelerated healing of chemical burns, Int. J. Mol. Sci. 2023, 24(4), 4102.

3. Ningfei Shen, Anna Polyanskaya, Xiaoli Qi, Aya Al Othman, Anastasia Permyakova, Marina V. Volkova, Alexandre Mezentsev, Mikhail O. Durymanov*, Modification of mesenchymal stromal cells with silibinin-loaded PLGA nanoparticles improves their therapeutic efficacy for cutaneous wound repair, Nanomedicine, 2024, 61, 102767.

Introduction

Transplantation of autologous or allogeneic cells is a promising technique for regenerative medicine to restore or replace damaged or diseased cells or tissue. A number of cell therapies in the field of regenerative medicine are now either established practices or FDA-approved for commercial use, including skin substitutes derived from fibroblasts for the therapy of diabetic foot ulcers or burns, scaffolds containing keratinocytes and fibroblasts for surgically generated vascular wound bed treatment, and others [1]. Fibroblasts hold great application potential in the area of tissue engineering and regenerative medicine due to their ability to synthesize and deposit extracellular matrix components [2]. MSCs are another promising candidate for regenerative therapy, owing mainly to their multi-lineage differentiation potential as well as secretory property. MSC-secreted factors regulate cell proliferation, direct migration, and initiate differentiation [3]. In regenerative applications, MSCs have demonstrated encouraging regenerative potential for treatment of osteoarthritis [4], Alzheimer's disease [5], deep burns [6], and mechanical wounds [7].

However, the low survival rate of fibroblasts and MSCs when transplanted into damaged or inflamed tissues is one of the major obstacles for their use in regenerative medicine. Following transplantation, the cells are exposed to severe environmental factors, such as oxidative stress, hypoxia, and ischemia. It was reported that MSCs are more sensitive to oxidative stress compared to other differentiated cell types, and excess intracellular ROS or endogenously induced oxidative stress impairs MSCs proliferation, self-renewal, and differentiation capacities [8]. In addition, excessive levels of oxidative stress can damage the transplanted cells, including their lipids, proteins, and DNA [9]. Approaches based on engineering provide solutions to overcome these limitations. In particular, the development of biomaterials has enabled the control of biophysical and biochemical properties of materials that can alter the behavior and function of the transplanted cells. Many biomaterials have been reported to improve the regenerative properties of MSCs and fibroblasts, ranging from natural to synthetic materials. For example, hydrogels can provide a tunable environment for extracellular matrix (ECM)

and cell-cell interactions.

The scientific significance of this study is the development of techniques to enhance the viability of fibroblasts and MSCs by modifying these cells with polymeric micro- or nanoparticles containing cytoprotective molecules. Peroxiredoxin-1 (Prx1) is a multifunctional protein, that is normally expressed intracellularly and plays a dual role of molecular chaperone and peroxidase. In this study, Prx1-loaded PLGA-based microparticles were covalently attached to the fibroblast cell surface, providing sustained Prx1 release. The released protein interacted with TLR4 receptors on the fibroblast surface in a pseudoautocrine manner, resulting in improved fibroblast resistance to oxidative stress and their enhanced migration capacity. To improve the regenerative potential of MSCs, the cells were modified via endocytic uptake by SBN-loaded PLGA nanoparticles. SBN is a phytochemical and antioxidant, that activates the Nrf2-Keap1 signaling pathway responsible for cell survival under oxidative stress. In turn, the modification of MSCs with PLGA/SBN nanoparticles improved the cell survival and wound healing effects after cells were transplanted into the area of damaged tissue, which has been shown in experiments using an animal wound model.

Goal: To study the feasibility of intracellular and cell surface modification of living cells with cytoprotective polymeric microparticles to improve their regenerative properties.

Objectives:

• To synthesize Prx1-loaded PLGA microparticles capable of sustained Prx1 release and preservation of the bioactivity of released Prx1;

• To study the feasibility of fibroblast surface modification with Prx1-loaded PLGA microparticles to enhance their regenerative properties;

• To synthesize SBN-loaded PLGA nanoparticles, which can be effectively internalized by MSCs;

• To investigate the mechanism by which PLGA/SBN nanoparticles protect MSCs from oxidative stress;

• To investigate the viability of MSCs modification with PLGA/SBN nanoparticles

to enhance regenerative properties, and to determine the function of these modified MSCs in the cutaneous wound healing process in a mouse model.

Заключение диссертации по теме «Другие cпециальности», Шэнь Нинфей

Conclusions

This dissertation introduced two non-genetic cell modification strategies, namely loading drug-encapsulated synthetic carriers "onto" the 3T3 fibroblast cell surface by covalent binding and "into" MSCs by cellular internalization, in order to improve cell functions for regenerative medicine purposes.

• Synthesized PLGA/Prx1 microparticles exhibited a sustained protein release profile in the absence of toxic effects on 3T3 fibroblasts. Bioactivity of released Prx1 from PLGA microparticles has been demonstrated.

• Through the EDC/NHS reaction, PLGA/Prx1 particles adhered covalently to the 3T3 cell membrane. The procedure does not affect cell viability, and results in PLGA/Prx1 microparticles attachment to the cell surface without further uptake.

• PLGA/Prx1-modified 3T3 fibroblasts displayed an increase in survival rate under oxidative stress, enhanced cell mobility, increased collagen I generation, and reduced cell senescence in response to t-BHP-induced oxidative stress.

• PLGA/SBN nanoparticles could be rapidly internalized by MSCs via clathrin-mediated endocytosis. The internalized nanoparticles neutralized the intracellular ROS and protected cells from oxidative damage induced by t-BHP. The antioxidative protective mechanism of released SBN intracellularly lies in that released SBN could activate the Nrf2 signaling pathway, resulting in the generation of antioxidant proteins including NQO1, GSTP1, and Prx2.

• PLGA/SBN-modified MSCs accelerated wound closure and enhanced the grade of tissue repair when compared to wounds treated with empty HA hydrogel and unmodified MSCs. Only in the group treated with PLGA/SBN-modified MSCs were GFP-positive cells detected in the dermal layer of newly formed epidermis, indicating that this modification improved cell survival and retention after delivery.

• Additionally, the wound tissue treated with PLGA/SBN-modified MSCs showed a lower expression of cytokines and growth factors implicated in the inflammatory and proliferative phases of wound healing, indicating a greater degree of their completion. All of these contribute to enhanced wound healing.

In summary, we developed a novel method for modifying fibroblasts to improve their biological properties, which can be advantageous for wound repair, cosmetic dermatology, and tissue engineering. The modification of MSCs with SBN-loaded PLGA nanoparticles enhanced their viability when transplanted into full-thickness cutaneous lesions and accelerated wound healing. could be a promising method for accelerating wound recovery.

Список литературы диссертационного исследования кандидат наук Шэнь Нинфей, 2025 год

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