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Hyaluronidase-Responsive Biomaterials

From EverybodyWiki Bios & Wiki


Hyaluronidase (HAase)-responsive biomaterials are materials that rely on the enzyme’s ability to degrade Hyaluronic Acid (HA) in order to change the shape and size of the material. This degradation has commonly been used to release therapeutic agents from their carriers. Most HAase-responsive systems utilize HA coatings and the overexpression of HAase at target sites to create controlled-release drug delivery systems. These types of systems are of great interest to the pharmacoengineering field because unlike standard drug administrations they create less toxic side effects, increase the accumulation of drug at target sites, and provide a more sustained and constant release of drug. While these systems can theoretically be used for the treatment of any condition that results in the overexpression of HAase, the main uses are delivering therapeutic agents to tumors and bacterial infections. In addition, these systems have been used in conjunction with other newer therapies such as photodynamic therapy (PDT) and photothermal therapy (PTT).

Hyaluronic Acid and Hyaluronidase Interaction

HA is a natural polysaccharide that is a critical component of the extracellular matrix (ECM). HA is made up of repeating disaccharide units of D-glucuronic acid and β-acetylglucosamine.[1]. This linear polymer is an ideal biomaterial because it is non-toxic, biodegradable, and very hydrophilic. Another advantageous feature of HA is that its’ main receptor is Cluster of differentiation 44 (CD44), a common receptor protein. This receptor-HA interaction is involved in many processes such as wound healing, morphogenesis, and cancer [2]

HAase is a critical enzyme that degrades HA both frequently and efficiently in the body. It does this by cleaving the β-N-acetyl-D-glucosaminidic bond in the HA chain [3]. HAase naturally resides in both organs (spleen, skin, eyes, liver, testis, kidneys, uterus) and bodily fluids (blood, tears, and semen) [4]. There are six main types of HAase, appropriately named HAase 1-6. HAase 1 and HAase 2 are the main enzymes that hydrolyze HA, but they do this in different ways. HAase 1 degrades fragmented HA into oligo-HA, while HAase 2 breaks HA that is bound to CD44 into intermediate fragments that are then internalized to the endolysosomal compartment [5]. Elevated HAase levels have been linked to tumor malignancy, metastasis, and bacterial infections[6].

Synthesis of Hyaluronidase-Responsive Biomaterials

To create HAase-responsive biomaterials, HA has to be linked in some way to the biomaterial. Fortunately, HA has multiple mechanisms of incorporation. The main method includes modifying the backbone of HA to increase local hydrophobicity; therefore, making HA amphiphilic[7]. This local hydrophobicity allows the polysaccharide to bind hydrophobic drugs or therapeutic agents. In addition, the amphiphilic nature allows HA nanoparticles to self-assemble. One way to create local hydrophobicity is to utilize the many functional groups of HA. HA contains hydroxyl, aldehyde, and carboxylic groups[8]. However, care must be taken when deciding which functional group to use and at what concentration. For example, when the carboxyl group is modified, the circulation time is extended, but the targeting of HA is thereby limited[9]. While Hydroxyl groups, when used for nanoparticle incorporation, enhance the targeting ability of HA [10]. Some hydrophobic moieties that have been linked to HA to form self-assembling nanoparticles are long-chain alkyl amines [11], ceramides (CE) [12], and deoxycholic acid (DOCA) [13]. An additional method of creating hydrophobic regions is by creating an HA-copolymer. The attached polymer is typically hydrophobic and makes up the core of the particles, so hydrophobic therapeutic agents can be loaded [14]. The outer shell consists of the hydrophilic HA and acts as the targeting agent and drug release preventative agent. A common polymer that has been incorporated into HA is poly (D,L-lactideco-glycolide) (PLGA)[15]. The incorporation of the polymer can be done multiple ways. A polymer can be grafted directly onto the HA backbone as short or long branches[16] or a block polymer can be created with HA by inserting long polymer sequences in line with the HA sequences[17]. In addition, HA can also be bound to things through electrostatic interactions. HA is negatively charged; therefore, it naturally complexes with polycations. Some past examples have included chitosan, ε-polylysine (EPL) and polyethyleneimine (PEI) [18]. The main advantage of this strategy is that the HA structure is not compromised [19]. However, these particles often have to have additional stabilizing factors such as disulfide [20] and HA-L-histidine 9 [21] in order to be functional. All of these modifications can be done to different types of biomaterials to make them HAase responsive inlcuding nanoparticles, hydrogels, liposomes and inorganic nanoparticles[22] . In addition, this review will also highlight HA-responsive multilayered materials.

Hyaluronidase-Responsive Biomaterials Used to Treat Cancer

The cancer microenvironment consists of certain cell types, enzymes, ligands, pH levels, and many other factors that promote cancer cell growth. Not only are researchers trying to change these factors to create a less than desirable environment for cancer, but they are also using some of them to increase the amount of therapy that is delivered to the tumor site and decrease any premature drug release or off-targeting. Especially when treating cancer with standard chemotherapy, targeting is of the utmost importance because chemotherapy kills both cancerous cells and healthy cells. To create drug delivery systems that have controlled targeting and release modalities, two characteristics of the microenvironment have been utilized: elevated HAase levels and CD44 overexpression. HAase is elevated in cancerous cells to expedite HA degradation [23]. In fact, the concentration of HAase is 200-1000 times higher in cancerous tissues than in normal tissues[24]. Given that both the HA receptor, CD44, and the enzyme that degrades HA, HAase, are both upregulated in certain cancers such as breast, colon, and lung [25], HA is an obvious choice for biomaterial coating and conjugation in drug delivery systems. The basic mechanism for HA-conjugated/coated nanoparticles is to first target CD44+ cancerous cells and enter those cells via CD44-mediated receptor endocytosis [26]. Once inside the cell, the high levels of HAase will degrade the HA shell or linker; thereby, releasing the therapeutic agents loaded in the core. HAase responsive biomaterials have been mainly researched for the treatment of colon cancer and breast cancer.

Colon Cancer

Colon cancer is the third most common cause of cancer-related deaths, and in 2022 it is expected to take 52,850 more lives [27]. Given chemotherapy’s many drawbacks, alternative drug delivery systems have been developed to either replace chemotherapy or be used alongside it. Specifically, Mesoporous Silica Nanoparticles (MSNs) have been of strong interest due to their biocompatibility, well-defined and well-tuned pore structure, and easily modifiable surface layer[28] [29]. The limitation of these particles is that the internal contents can leak out of the pores before reaching their destination leading to low therapeutic indices at the tumor site and possible systemic side effects[30] . To fix these issues, researchers have utilized HA to prevent premature release as well as provide a well-established targeting technique. For example, Zhang et al. developed a dual-stimulus drug delivery system that is triggered by biotin and HAase at the tumor site[31]. Biotin, a B-complex vitamin, has been shown to be upregulated in colon cancer in addition to HAase [32]. The MSN in this study was modified with desthiobiotin, streptavidin (SA), and HA. Desthiobiotin loosely bound the SA to clog the MSN pores while the nanoparticle traveled through the blood stream. The SA acted as an additional targeting agent because of its high affinity for biotin. HA was used as both a targeting agent for CD44+ cells and an easily degradable material that would only degrade in the presence of HAase. In vivo, the nanoparticles would target the CD44+ cells, attach to the receptor, and enter the cell via endocytosis. HAase would then degrade the HA coating releasing doxorubicin hydrochloride, a common drug used to kill cancer cells. Their results indicated that drug release was dependent on biotin and HAase levels, and that these nanoparticles were efficient at entering and killing Colon-6 and HT-29 cells. In addition to their in vitro experiments, BALB/c mice infected with Colon-6 cells were used as in vivo tumor models. They saw that mice treated with the HA-conjugated doxorubicin-loaded MSNs showed the most efficient tumor size reduction. These promising results were followed up by other researchers utilizing HAase responsive MSNs with other cancer treating drugs. For example, Jiang et al. loaded HA-conjugated MSNs with 5-fluorouracil, a broad-spectrum anticancer drug[33]. In this paper, HA was used as both a targeting agent and a preventative agent for premature release. The mechanism for these nanoparticles was a simplified version of Zhang et al.’s mechanism where CD44+ cells were targeted and entered via endocytosis of the nanoparticles. This was followed by HA degradation via HAase and subsequent drug release. Their results supported the findings of Zhang et al. because their HA-conjugated MSNs were 3-fold more effective at reducing tumor burden in BALB/c mice than free drug. While these results are promising, additional experiments are needed to ensure the safety and efficacy of these HAase-responsive drug delivery systems.

Breast Cancer

In 2021, breast cancer became the most commonly diagnosed cancer globally[34], and in 2022, 43,250 women in the United States are expected to die from breast cancer World Health Organization (2021-03-26). "Breast cancer". World Health Organization. Retrieved 2022-04-11.. These frightening statistics are what drives researchers to find better ways to treat this type of cancer. As mentioned previously, breast cancer tumors have elevated HAase levels and are CD44+ meaning HA can be used to both target the tumor and control drug release. One research team utilized both the high levels of HAase and the slightly acidic pH to control drug release when targeting cancer stem cells [35]. Cancer stem cells are the cause of recurrence and metastasis; and therefore, need to be targeted and killed. Li et al. modified previously developed Thioridazine (Thz)-loaded pH-sensitive PEG-poly (β-amino ester) (PEG-PBAE) micelles (PPM) with HA to add both a targeting element and an additional drug release control. Thz is an antipsychotic drug that has been used to inhibit cancer stem cells[36][37][38]. The proposed mechanism for this nanoparticle involved HA targeting the CD44 receptors on breast cancer stem cells and being endocytosed. The nanoparticles would then enter the lysosome where HAase would degrade the HA outer coating, the PBAE would be protonated breaking up the inner coating, and the Thz in the core would be released. They analyzed the cellular uptake, cytotoxicity, and lysosomal escape of the particles using human breast cancer cells (MCF-7). They also analyzed the in vivo antitumor efficiency in MCF-7 inoculated BALB/c nude mice. Their results indicated that the nanoparticles were effective at targeting CD44+ cells, and that the HA coating did not interact with the pH-responsiveness. In addition, the dual-responsive nanoparticles administered alongside a standard cancer treatment, doxorubicin, showed significant inhibition of the tumor as opposed to free doxorubicin and Thz. Another study focused on the size aspect of nanoparticles for treating breast cancer. The size of nanoparticles does matter. If the nanoparticles are too large, they will not penetrate the tumor deeply enough, and if they are too small, they will be cleared rapidly form the body. Given this restraint, a size changing particle that starts out large enough to not be cleared by the mononuclear-phagocyte system (MPS) but become small enough to penetrate the tumor would be ideal. Yu et al. created an HAase-responsive drug delivery system that combined three main methods of attack: chemotherapy, immune therapy, and photodynamic therapy [39]. Briefly, cationized gold nanoclusters were coated in HA, and then surrounded by a red blood cell coating. The HA coat would assist with targeting the nanoparticles to the tumor site and then degrade once at the tumor due to high levels of HAase. The red blood cell coating would help by extending circulation time [40][41]. Within these shells, there was a small core loaded with photosensitizer pheophorbide A, reactive oxygen species (ROS) responsive pro drug PXTK, and anti-PD-L1 peptide (dPPA). This core would kill cancer cells through the photosensitizer transforming surrounding oxygen into ROS, ROS triggering PXTK to be released, and the dPPA targeting the PD-1/PD-L1 pathway relieving the immunosuppressive environment of the tumor. Researchers found that particles originating in a size of 150 nm had the best tumor targeting ability, and that under irradiation, the PXTK was released successfully. In addition, the host immune response was stimulated. All of this led to increased tumor inhibition in 4T1 tumor bearing female BALB/c mice. These types of combinational therapies show great promise for treating breast cancer and preventing metastasis.

Hyaluronidase-Responsive Biomaterials Used to Treat/Prevent Bacterial Infections

Another application of HAase responsive delivery systems is the delivery of antibiotics which can be used to prevent or treat bacterial infections. After bacteria bind to surfaces, they secrete enzymes to be able to spread further [42] . One of these enzymes is HAase which degrades critical ECM components making it easier for the bacteria to infiltrate [43]. This enzyme has been shown to be produced by multiple Gram-positive bacteria including Staphylococcus aureus (S. aureus) , Streptococcus, and Clostridium [44]. Given the occurrence and danger of bacterial infections, bioactive solutions that promptly respond when bacteria infiltrate are necessary. Baier et al. set out to engineer HA-based nanocapsules that could coat plastic materials and wound dressings[45]. These nanocapsules would degrade in the presence of HAase secreted by invading S. aureus bacteria and release polyhexanide, a common disinfectant and antiseptic. Their preliminary results indicated that polyhexanide was released only in the presence of S. aureus, and that the nanocapsules were able to efficiently kill both S. Aureus and Escherichia coli (E. Coli). Another researcher used a different approach to treating infections. Yuwen et al. focused on methicillin-resistant S. Aureus (MRSA) given the threat that antibiotic resistance poses to public health[46]. Their HAase-responsive system combined PDT and fluorescent imaging to both detect and treat the infection. Briefly, HA was conjugated to Chlorin e6 (Ce6), a photosensitizer and fluorescent probe. This compound was then assembled onto the surface of Molybdenum disulfide (MoS2) nanosheets. MoS2 would quench the fluorescence of Ce6 when in close contact. Once HAase degraded the HA, Ce6 would be released and its’ fluorescence and photodynamic property would be restored. To treat the infection, both PDT and PTT would be used. In the presence of near infrared light, free Ce6 and MoS2 absorb light energy and convert those to ROS and heat, respectively. Both ROS and heat kill bacteria. Promising in vivo results indicated that 99.9% of the bacteria were killed in MRSA infected tissues. In addition to nanoparticles, multilayers can also be HAase-responsive. Sutrisno et al. utilized HAase-responsive multilayers to help prevent biofilm formation on orthopedic implants [47]. Given that infection is the most common cause of implant failure, antibacterial coatings have been extensively researched[48]. One possible coating material is HA which can be degraded upon bacterial infiltration. To create the coating, chitosan/sodium hyaluronate-lauric acid (SL) were loaded onto bone morphogenetic protein 2 (BMP2) loaded titanium nanotubes (TNT). Both Sodium hyaluronate and lauric acid (LA) were used because Sodium Hyaluronate can be degraded by HAase and it prevents bacterial adhesion[49][50] while LA disrupts bacterial membranes thereby killing them[51][52]. The proposed mechanism is that SL multilayers will be degraded by HAase; thereby, releasing LA and stimulating the release of BMP2 to induce osteoblast differentiation. In vitro results indicated that the antibacterial multilayers reduced the growth of bacteria as well as enhanced osteoblast gene expression. In addition, the release of LA only happened in the presence of HAase because the negative control, E. Coli, did not stimulate any multilayer release. Another multilayer approach used layers of polyacrylic acid (PAA) , chitosan quaternary ammonium salt, gentamicin sulfate (GS), and HA to create a surface that controls drug release based on two factors: pH and HAase levels [53]. When bacteria infiltrate, the pH slightly rises [54]. This slight increase in pH will make the multilayer swell and promote drug release. In addition, the HAase released by bacteria will degrade the HA further contributing to drug distribution. This system had exciting in vitro results showing a higher than 99% antibacterial efficiency. These results demonstrate how HAase can be used as both nanoparticles and multilayered biomaterials to fight off infection.


This article "Hyaluronidase-Responsive Biomaterials" is from Wikipedia. The list of its authors can be seen in its historical and/or the page Edithistory:Hyaluronidase-Responsive Biomaterials. Articles copied from Draft Namespace on Wikipedia could be seen on the Draft Namespace of Wikipedia and not main one.

  1. ↑ Li, Mengqian; Zhao, Guangkuo; Su, Wei-Ke; Shuai, Qi (2020). "Enzyme-Responsive Nanoparticles for Anti-tumor Drug Delivery". Frontiers in Chemistry. 8: 647. Bibcode:2020FrCh....8..647S. doi:10.3389/fchem.2020.00647. ISSN 2296-2646. PMC 7406800 Check |pmc= value (help). PMID 32850662 Check |pmid= value (help).
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  3. ↑ Choi, Ki Young; Han, Hwa Seung; Lee, Eun Sook; Shin, Jung Min; Almquist, Benjamin D.; Lee, Doo Sung; Park, Jae Hyung (2019-08-01). "Hyaluronic Acid–Based Activatable Nanomaterials for Stimuli-Responsive Imaging and Therapeutics: Beyond CD44-Mediated Drug Delivery". Advanced Materials. 31 (34): 1803549. Bibcode:2019AdM....3103549C. doi:10.1002/adma.201803549. hdl:10044/1/66918. ISSN 0935-9648. PMID 30773699. Unknown parameter |s2cid= ignored (help)
  4. ↑ Jung, Hyunwook (2020-07-15). "Hyaluronidase: An overview of its properties, applications, and side effects". Archives of Plastic Surgery. 47 (4): 297–300. doi:10.5999/aps.2020.00752. ISSN 2234-6163. PMC 7398804 Check |pmc= value (help). PMID 32718106 Check |pmid= value (help).
  5. ↑ Bourguignon, Lilly YW; Singleton, Patrick A.; Diedrich, Falko; Stern, Robert; Gilad, Eli (2004). "CD44 interaction with Na+-H+ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion". Journal of Biological Chemistry. 279 (26): 26991–27007. doi:10.1074/jbc.M311838200. PMID 15090545.
  6. ↑ Choi, Ki Young; Han, Hwa Seung; Lee, Eun Sook; Shin, Jung Min; Almquist, Benjamin D.; Lee, Doo Sung; Park, Jae Hyung (2019-08-01). "Hyaluronic Acid–Based Activatable Nanomaterials for Stimuli-Responsive Imaging and Therapeutics: Beyond CD44-Mediated Drug Delivery". Advanced Materials. 31 (34): 1803549. Bibcode:2019AdM....3103549C. doi:10.1002/adma.201803549. hdl:10044/1/66918. ISSN 0935-9648. PMID 30773699. Unknown parameter |s2cid= ignored (help)
  7. ↑ Cai, Jia; Fu, Jingru; Li, Ruirui; Zhang, Fang; Ling, Guixia; Zhang, Peng (2019-03-15). "A potential carrier for anti-tumor targeted delivery-hyaluronic acid nanoparticles". Carbohydrate Polymers. 208: 356–364. doi:10.1016/j.carbpol.2018.12.074. ISSN 0144-8617. PMID 30658811. Unknown parameter |s2cid= ignored (help)
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  9. ↑ Cai, Jia; Fu, Jingru; Li, Ruirui; Zhang, Fang; Ling, Guixia; Zhang, Peng (2019-03-15). "A potential carrier for anti-tumor targeted delivery-hyaluronic acid nanoparticles". Carbohydrate Polymers. 208: 356–364. doi:10.1016/j.carbpol.2018.12.074. ISSN 0144-8617. PMID 30658811. Unknown parameter |s2cid= ignored (help)
  10. ↑ Cai, Jia; Fu, Jingru; Li, Ruirui; Zhang, Fang; Ling, Guixia; Zhang, Peng (2019-03-15). "A potential carrier for anti-tumor targeted delivery-hyaluronic acid nanoparticles". Carbohydrate Polymers. 208: 356–364. doi:10.1016/j.carbpol.2018.12.074. ISSN 0144-8617. PMID 30658811. Unknown parameter |s2cid= ignored (help)
  11. ↑ Vafaei, Seyed Yaser; Esmaeili, Motahareh; Amini, Mohsen; Atyabi, Fatemeh; Ostad, Seyed Naser; Dinarvand, Rassoul (2016-06-25). "Self assembled hyaluronic acid nanoparticles as a potential carrier for targeting the inflamed intestinal mucosa". Carbohydrate Polymers. 144: 371–381. doi:10.1016/j.carbpol.2016.01.026. ISSN 0144-8617. PMID 27083829.
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  13. ↑ Li, Jing; Huo, Meirong; Wang, Jing; Zhou, Jianping; Mohammad, Jumah M.; Zhang, Yinlong; Zhu, Qinnv; Waddad, Ayman Y.; Zhang, Qiang (2012-03-01). "Redox-sensitive micelles self-assembled from amphiphilic hyaluronic acid-deoxycholic acid conjugates for targeted intracellular delivery of paclitaxel". Biomaterials. 33 (7): 2310–2320. doi:10.1016/j.biomaterials.2011.11.022. ISSN 0142-9612. PMID 22166223.
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  15. ↑ Cai, Jia; Fu, Jingru; Li, Ruirui; Zhang, Fang; Ling, Guixia; Zhang, Peng (2019-03-15). "A potential carrier for anti-tumor targeted delivery-hyaluronic acid nanoparticles". Carbohydrate Polymers. 208: 356–364. doi:10.1016/j.carbpol.2018.12.074. ISSN 0144-8617. PMID 30658811. Unknown parameter |s2cid= ignored (help)
  16. ↑ Lee, Hyukjin; Ahn, Cheol-Hee; Park, Tae Gwan (2009-04-08). "Poly[lactic-co-(glycolic acid)]-Grafted Hyaluronic Acid Copolymer Micelle Nanoparticles for Target-Specific Delivery of Doxorubicin". Macromolecular Bioscience. 9 (4): 336–342. doi:10.1002/mabi.200800229. ISSN 1616-5187. PMID 19006195.
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  18. ↑ Cai, Jia; Fu, Jingru; Li, Ruirui; Zhang, Fang; Ling, Guixia; Zhang, Peng (2019-03-15). "A potential carrier for anti-tumor targeted delivery-hyaluronic acid nanoparticles". Carbohydrate Polymers. 208: 356–364. doi:10.1016/j.carbpol.2018.12.074. ISSN 0144-8617. PMID 30658811. Unknown parameter |s2cid= ignored (help)
  19. ↑ Li, Wenhao; Yi, Xiaoli; Liu, Xing; Zhang, Zhirong; Fu, Yao; Gong, Tao (2016-03-10). "Hyaluronic acid ion-pairing nanoparticles for targeted tumor therapy". Journal of Controlled Release. 225: 170–182. doi:10.1016/j.jconrel.2016.01.049. ISSN 0168-3659. PMID 26826304.
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  22. ↑ Choi, Ki Young; Han, Hwa Seung; Lee, Eun Sook; Shin, Jung Min; Almquist, Benjamin D.; Lee, Doo Sung; Park, Jae Hyung (2019-08-01). "Hyaluronic Acid–Based Activatable Nanomaterials for Stimuli-Responsive Imaging and Therapeutics: Beyond CD44-Mediated Drug Delivery". Advanced Materials. 31 (34): 1803549. Bibcode:2019AdM....3103549C. doi:10.1002/adma.201803549. hdl:10044/1/66918. ISSN 0935-9648. PMID 30773699. Unknown parameter |s2cid= ignored (help)
  23. ↑ Cai, Jia; Fu, Jingru; Li, Ruirui; Zhang, Fang; Ling, Guixia; Zhang, Peng (2019-03-15). "A potential carrier for anti-tumor targeted delivery-hyaluronic acid nanoparticles". Carbohydrate Polymers. 208: 356–364. doi:10.1016/j.carbpol.2018.12.074. ISSN 0144-8617. PMID 30658811. Unknown parameter |s2cid= ignored (help)
  24. ↑ Lokeshwar, Vinata B.; Mirza, Summan; Jordan, Andre (2014). "Targeting hyaluronic acid family for cancer chemoprevention and therapy". Advances in Cancer Research. 123: 35–65. doi:10.1016/B978-0-12-800092-2.00002-2. ISBN 9780128000922. PMC 4791948. PMID 25081525.
  25. ↑ Choi, Ki Young; Han, Hwa Seung; Lee, Eun Sook; Shin, Jung Min; Almquist, Benjamin D.; Lee, Doo Sung; Park, Jae Hyung (2019-08-01). "Hyaluronic Acid–Based Activatable Nanomaterials for Stimuli-Responsive Imaging and Therapeutics: Beyond CD44-Mediated Drug Delivery". Advanced Materials. 31 (34): 1803549. Bibcode:2019AdM....3103549C. doi:10.1002/adma.201803549. hdl:10044/1/66918. ISSN 0935-9648. PMID 30773699. Unknown parameter |s2cid= ignored (help)
  26. ↑ Li, Weinan; Zhang, Xiaoyu; Nan, Yang; Jia, Li; Sun, Jialin; Zhang, Lina; Wang, Yanhong (2021). "Hyaluronidase and pH Dual-Responsive Nanoparticles for Targeted Breast Cancer Stem Cells". Frontiers in Oncology. 11: 760423. doi:10.3389/fonc.2021.760423. ISSN 2234-943X. PMC 8739758 Check |pmc= value (help). PMID 35004281 Check |pmid= value (help).
  27. ↑ "Colorectal Cancer Statistics | How Common Is Colorectal Cancer?". Retrieved 2022-04-11.
  28. ↑ Zhao, Qinfu; Geng, Hongjian; Wang, Ying; Gao, Yikun; Huang, Jiahao; Wang, Yan; Zhang, Jinghai; Wang, Siling (2014-11-26). "Hyaluronic Acid Oligosaccharide Modified Redox-Responsive Mesoporous Silica Nanoparticles for Targeted Drug Delivery". ACS Applied Materials & Interfaces. 6 (22): 20290–20299. doi:10.1021/am505824d. ISSN 1944-8244. PMID 25311422.
  29. ↑ Zhao, Qinfu; Liu, Jia; Zhu, Wenquan; Sun, Changshan; Di, Donghua; Zhang, Ying; Wang, Pu; Wang, Zhanyou; Wang, Siling (September 2015). "Dual-stimuli responsive hyaluronic acid-conjugated mesoporous silica for targeted delivery to CD44-overexpressing cancer cells". Acta Biomaterialia. 23: 147–156. doi:10.1016/j.actbio.2015.05.010. ISSN 1878-7568. PMID 25985912.
  30. ↑ Jiang, Haiping; Shi, Xinyan; Yu, Xiaoyun; He, Xinjia; An, Yongheng; Lu, Haijun (2018-02-23). "Hyaluronidase Enzyme-responsive Targeted Nanoparticles for Effective Delivery of 5-Fluorouracil in Colon Cancer". Pharmaceutical Research. 35 (4): 73. doi:10.1007/s11095-017-2302-4. ISSN 1573-904X. PMID 29476264. Unknown parameter |s2cid= ignored (help)
  31. ↑ Zhang, Mingzhen; Xu, Changlong; Wen, Liuqing; Han, Moon K.; Xiao, Bo; Zhou, Jun; Zhang, Yuchen; Zhang, Zhan; Viennois, Emilie; Merlin, Didier (2016). "A Hyaluronidase-Responsive Nanoparticle-Based Drug Delivery System for Targeting Colon Cancer Cells". Cancer Research. 76 24 (24): 7208–7218. doi:10.1158/0008-5472.CAN-16-1681. PMC 5161640. PMID 27742685.
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  33. ↑ Jiang, Haiping; Shi, Xinyan; Yu, Xiaoyun; He, Xinjia; An, Yongheng; Lu, Haijun (2018-02-23). "Hyaluronidase Enzyme-responsive Targeted Nanoparticles for Effective Delivery of 5-Fluorouracil in Colon Cancer". Pharmaceutical Research. 35 (4): 73. doi:10.1007/s11095-017-2302-4. ISSN 1573-904X. PMID 29476264. Unknown parameter |s2cid= ignored (help)
  34. ↑ World Health Organization (2021-03-26). "Breast cancer". World Health Organization. Retrieved 2022-04-11.
  35. ↑ Li, Weinan; Zhang, Xiaoyu; Nan, Yang; Jia, Li; Sun, Jialin; Zhang, Lina; Wang, Yanhong (2021). "Hyaluronidase and pH Dual-Responsive Nanoparticles for Targeted Breast Cancer Stem Cells". Frontiers in Oncology. 11: 760423. doi:10.3389/fonc.2021.760423. ISSN 2234-943X. PMC 8739758 Check |pmc= value (help). PMID 35004281 Check |pmid= value (help).
  36. ↑ Gil-Ad, Irit; Shtaif, Biana; Levkovitz, Yechiel; Dayag, Michal; Zeldich, Ella; Weizman, Abraham (2004-03-01). "Characterization of phenothiazine-induced apoptosis in neuroblastoma and glioma cell lines". Journal of Molecular Neuroscience. 22 (3): 189–198. doi:10.1385/JMN:22:3:189. ISSN 1559-1166. PMID 14997012. Unknown parameter |s2cid= ignored (help)
  37. ↑ Kang, Sokbom; Dong, Seung Myung; Kim, Boh-Ram; Park, Mi Sun; Trink, Barry; Byun, Hyun-Jung; Rho, Seung Bae (September 2012). "Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells". Apoptosis: An International Journal on Programmed Cell Death. 17 (9): 989–997. doi:10.1007/s10495-012-0717-2. ISSN 1573-675X. PMC 3413814. PMID 22460505.
  38. ↑ Strobl, J. S.; Kirkwood, K. L.; Lantz, T. K.; Lewine, M. A.; Peterson, V. A.; Worley, J. F. (1990-09-01). "Inhibition of human breast cancer cell proliferation in tissue culture by the neuroleptic agents pimozide and thioridazine". Cancer Research. 50 (17): 5399–5405. ISSN 0008-5472. PMID 2386945.
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  40. ↑ Fang, Ronnie Hongbo; Hu, Che-Ming Jack; Zhang, Liangfang (April 2012). "Nanoparticles disguised as red blood cells to evade the immune system". Expert Opinion on Biological Therapy. 12 (4): 385–389. doi:10.1517/14712598.2012.661710. ISSN 1744-7682. PMID 22332936. Unknown parameter |s2cid= ignored (help)
  41. ↑ Gao, Weiwei; Hu, Che-Ming J; Fang, Ronnie H; Luk, Brian T; Su, Jing; Zhang, Liangfang (2013-07-12). "Surface functionalization of gold nanoparticles with red blood cell membranes". Advanced Materials (Deerfield Beach, Fla.). 25 (26): 3549–3553. Bibcode:2013AdM....25.3549G. doi:10.1002/adma.201300638. ISSN 1521-4095. PMC 4138311. PMID 23712782.
  42. ↑ Robert Stern (2009). Hyaluronan in Cancer Biology (First ed.). Academic Press-Elsevier. Search this book on
  43. ↑ Steven Percival; Keith Cutting (2019-08-21). Microbiology of Wounds. CRC Press. ISBN 978-0-367-38420-3. Search this book on
  44. ↑ Hynes, Wayne L.; Walton, Sheryl Lynne (2000-02-01). "Hyaluronidases of Gram-positive bacteria". FEMS Microbiology Letters. 183 (2): 201–207. doi:10.1111/j.1574-6968.2000.tb08958.x. ISSN 0378-1097. PMID 10675584. Unknown parameter |s2cid= ignored (help)
  45. ↑ Baier, Grit; Cavallaro, Alex; Vasilev, Krasimir; Mailänder, Volker; Musyanovych, Anna; Landfester, Katharina (2013-04-08). "Enzyme Responsive Hyaluronic Acid Nanocapsules Containing Polyhexanide and Their Exposure to Bacteria To Prevent Infection". Biomacromolecules. 14 (4): 1103–1112. doi:10.1021/bm302003m. ISSN 1525-7797. PMID 23448580.
  46. ↑ Yuwen, Lihui; Qiu, Qiu; Xiu, Weijun; Yang, Kaili; Li, Yuqing; Xiao, Hang; Yang, Wenjing; Yang, Dongliang; Wang, Lianhui (2021). "Hyaluronidase-responsive phototheranostic nanoagents for fluorescence imaging and photothermal/photodynamic therapy of methicillin-resistant Staphylococcus aureus infections". Biomaterials Science. 9 (12): 4484–4495. doi:10.1039/D1BM00406A. ISSN 2047-4830. PMID 34002742 Check |pmid= value (help). Unknown parameter |s2cid= ignored (help)
  47. ↑ Sutrisno, Linawati; Hu, Yan; Shen, Xinkun; Li, Menghuan; Luo, Zhong; Dai, Liangliang; Wang, Sixiang; Zhong, Julia Li; Cai, Kaiyong (2018-08-01). "Fabrication of hyaluronidase-responsive biocompatible multilayers on BMP2 loaded titanium nanotube for the bacterial infection prevention". Materials Science and Engineering: C. 89: 95–105. doi:10.1016/j.msec.2018.03.024. ISSN 0928-4931. PMID 29752124. Unknown parameter |s2cid= ignored (help)
  48. ↑ Del Pozo, Jose L; Patel, Robin (2009-08-20). "Clinical practice. Infection associated with prosthetic joints". The New England Journal of Medicine. 361 (8): 787–794. doi:10.1056/NEJMcp0905029. ISSN 1533-4406. PMC 2850113. PMID 19692690.
  49. ↑ Chua, Poh-Hui; Neoh, Koon-Gee; Kang, En-Tang; Wang, Wilson (2008-04-01). "Surface functionalization of titanium with hyaluronic acid/chitosan polyelectrolyte multilayers and RGD for promoting osteoblast functions and inhibiting bacterial adhesion". Biomaterials. 29 (10): 1412–1421. doi:10.1016/j.biomaterials.2007.12.019. ISSN 0142-9612. PMID 18190959.
  50. ↑ Shen, Xinkun; Zhang, Fei; Li, Ke; Qin, Chenhu; Ma, Pingping; Dai, Liangliang; Cai, Kaiyong (2016-02-15). "Cecropin B loaded TiO2 nanotubes coated with hyaluronidase sensitive multilayers for reducing bacterial adhesion". Materials & Design. 92: 1007–1017. doi:10.1016/j.matdes.2015.12.126. ISSN 0264-1275.
  51. ↑ Jackman, Joshua A.; Yoon, Bo Kyeong; Li, Danlin; Cho, Nam-Joon (2016-03-03). "Nanotechnology Formulations for Antibacterial Free Fatty Acids and Monoglycerides". Molecules (Basel, Switzerland). 21 (3): 305. doi:10.3390/molecules21030305. ISSN 1420-3049. PMC 6273827. PMID 26950108.
  52. ↑ Salleh, Eraricar; Muhammad, Ida Idayu; Pahlawi, Qadly Ameen (2014-01-01). "Spectrum Activity and Lauric Acid Release Behaviour of Antimicrobial Starch-based Film". International Conference and Workshop on Chemical Engineering UNPAR 2013 (ICCE UNPAR 2013). 9: 11–22. doi:10.1016/j.proche.2014.05.003. ISSN 1876-6196.
  53. ↑ Ayaz, Pirah; Xu, Bingjie; Zhang, Xiansheng; Wang, Jiping; Yu, Dan; Wu, Jindan (2020-10-15). "A pH and hyaluronidase dual-responsive multilayer-based drug delivery system for resisting bacterial infection". Applied Surface Science. 527: 146806. Bibcode:2020ApSS..52746806A. doi:10.1016/j.apsusc.2020.146806. ISSN 0169-4332. Unknown parameter |s2cid= ignored (help)
  54. ↑ Percival, Steven L.; McCarty, Sara; Hunt, John A.; Woods, Emma J. (2014-03-01). "The effects of pH on wound healing, biofilms, and antimicrobial efficacy". Wound Repair and Regeneration. 22 (2): 174–186. doi:10.1111/wrr.12125. ISSN 1067-1927. PMID 24611980. Unknown parameter |s2cid= ignored (help)

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