INTRODUCTION

Section:

ChooseTop of pageABSTRACTINTRODUCTION <<TYPES OF NANOPARTICLESLIPOSOMESPROTEIN-BASED NANOPARTICL...EXOSOMESCARBON-BASED NANOCARRIERSOS-TARGETED DRUG DELIVERY...CELL MEMBRANE-BASED NANOP...STIMULI-RESPONSIVE NANOMA...CHALLENGES AND OUTLOOKOsteosarcoma (OS), the most common and severe primary malignant bone tumor, is composed of spindle cells that produce osteoid and predominantly initiates in the metaphysis of the long bones with a high occurrence in adolescents and young adults.11. H. K. Brown, M. Tellez-Gabriel, and D. Heymann, “ Cancer stem cells in osteosarcoma,” Cancer Lett. 386, 189–195 (2017). https://doi.org/10.1016/j.canlet.2016.11.019 It is a highly aggressive tumor and initiates as a monoclonal disease, rapidly developing into a polyclonal one, and is considered one of the most complex tumors in molecular aberration.2,32. P. S. Meltzer and L. J. Helman, “ New horizons in the treatment of osteosarcoma,” N. Engl. J. Med. 385(22), 2066–2076 (2021). https://doi.org/10.1056/NEJMra21034233. C. Chen, Y. Guo, Q. Huang, B. Wang, W. Wang, J. Niu, J. Lou, J. Xu, T. Ren, Y. Huang, and W. Guo, “ PI3K inhibitor impairs tumor progression and enhances sensitivity to anlotinib in anlotinib-resistant osteosarcoma,” Cancer Lett. 536, 215660 (2022). https://doi.org/10.1016/j.canlet.2022.215660 Since the 1970s, with the introduction of extensive resection and neoadjuvant chemotherapy, the 5-year survival rate of patients with primary OS has increased from 17% to 67%, but is only 20%–30% in patients with concomitant lung metastases.4,54. C. Chen, H. Zhang, Y. Yu, Q. Huang, W. Wang, J. Niu, J. Lou, T. Ren, Y. Huang, and W. Guo, “ Chloroquine suppresses proliferation and invasion and induces apoptosis of osteosarcoma cells associated with inhibition of phosphorylation of STAT3,” Aging 13(13), 17901–17913 (2021). https://doi.org/10.18632/aging.2031965. M. Heng, A. Gupta, P. W. Chung, J. H. Healey, M. Vaynrub, P. S. Rose, M. T. Houdek, P. P. Lin, A. J. Bishop, F. J. Hornicek, Y. L. Chen, S. Lozano-Calderon, G. E. Holt, I. Han, D. Biau, X. Niu, N. M. Bernthal, P. C. Ferguson, and J. S. Wunder, “ The role of chemotherapy and radiotherapy in localized extraskeletal osteosarcoma,” Eur. J. Cancer 125, 130–141 (2020). https://doi.org/10.1016/j.ejca.2019.07.029 Chemotherapy can eradicate tumor deposits if it is initiated with a low disease burden. Responsiveness of OS to neoadjuvant chemotherapy is a major determinant of clinical outcome for most histologic subtypes, and it is usually defined by a histologic appearance in the resected specimen. The current standard care for OS consists of neoadjuvant chemotherapy (pre-operative), surgical resection, and adjuvant chemotherapy (post-operative).66. M. Argenziano, C. Tortora, E. Pota, A. Di Paola, M. Di Martino, C. Di Leva, D. Di Pinto, and F. Rossi, “ Osteosarcoma in children: Not only chemotherapy,” Pharmaceuticals 14(9), 923 (2021). https://doi.org/10.3390/ph14090923 However, there is no worldwide consensus on a standard chemotherapy approach for OS, and the development of adjuvant chemotherapy has been largely empiric, with the majority of regimens incorporating doxorubicin, cisplatin, and methotrexate or ifosfamide despite the associated drug-related toxicity such as cardiotoxicity and nephrotoxicity.7,87. R. Belayneh, M. S. Fourman, S. Bhogal, and K. R. Weiss, “ Update on osteosarcoma,” Curr. Oncol. Rep. 23(6), 71 (2021). https://doi.org/10.1007/s11912-021-01053-78. Y. Liu, Q. Li, Q. Bai, and W. Jiang, “ Advances of smart nano-drug delivery systems in osteosarcoma treatment,” J. Mater. Chem. B 9(27), 5439–5450 (2021). https://doi.org/10.1039/D1TB00566ADespite recent novel therapeutic developments for OS, such as immunotherapy, oncolytic virotherapy, and gene therapy, the ongoing challenges in overcoming metastatic OS warrant new approaches to improve overall patient survival, owing to the limited efficacy of chemotherapeutic agents, high level of heterogeneity, and multidrug resistance of OS.99. Y. Xin, Q. Huang, J. Q. Tang, X. Y. Hou, P. Zhang, L. Z. Zhang, and G. Jiang, “ Nanoscale drug delivery for targeted chemotherapy,” Cancer Lett. 379(1), 24–31 (2016). https://doi.org/10.1016/j.canlet.2016.05.023 Immunotherapy is highly effective in the treatment of tumors such as hematological malignancies and melanoma, but its therapeutic effect in most solid tumors such as OS is still uncertain.1010. C. Chen, L. Xie, T. Ren, Y. Huang, J. Xu, and W. Guo, “ Immunotherapy for osteosarcoma: Fundamental mechanism, rationale, and recent breakthroughs,” Cancer Lett. 500, 1–10 (2021). https://doi.org/10.1016/j.canlet.2020.12.024 Oncolytic virotherapy and gene therapy for OS is still in the research stage and cannot yet be used in the clinic. Targeted drugs such as apatinib, cabozantinib, and anlotinib only prolong the disease-free survival of OS patients, but not their overall survival.33. C. Chen, Y. Guo, Q. Huang, B. Wang, W. Wang, J. Niu, J. Lou, J. Xu, T. Ren, Y. Huang, and W. Guo, “ PI3K inhibitor impairs tumor progression and enhances sensitivity to anlotinib in anlotinib-resistant osteosarcoma,” Cancer Lett. 536, 215660 (2022). https://doi.org/10.1016/j.canlet.2022.215660 Prospects for novel drugs to effectively improve the prognosis of OS patients seemed rather bleak. Furthermore, the requisite high-dose chemotherapy often results in many acute and chronic side effects; hence, identifying novel strategies to amend the disease prognosis and the life expectancy of patients is necessary. Sometimes, a completely new treatment may not achieve immediate results, but it is an innovative and effective solution to improve on an existing treatment; it is time to think outside the lines. Approaches to enhance chemotherapy efficacy by improving delivery methods have yielded promising treatment results in recent years. The first approach attempted to target drug delivery for OS was intra-arterial chemotherapy administration using cisplatin.1111. N. Jaffe, J. Knapp, V. P. Chuang, S. Wallace, A. Ayala, J. Murray, A. Cangir, A. Wang, and R. S. Benjamin, “ Osteosarcoma: Intra-arterial treatment of the primary tumor with cis-diammine-dichloroplatinum II (CDP). Angiographic, pathologic, and pharmacologic studies,” Cancer 51(3), 402–407 (1983). https://doi.org/10.1002/1097-0142(19830201)51:3%3C402::AID-CNCR2820510308%3E3.0.CO;2-P This approach relies on the identification of a dose–response curve for OS to achieve high local drug concentration and tumor penetration that could be safely administered in venous infusions.The efficacy of chemotherapy for OS relies on the type of chemotherapy agent, concentration, and absorption efficiency. Meanwhile, the efficiency of drug distribution from plasma to the tumor is affected by some physiologic parameters, such as competitive drug uptake by the liver, excretion of small molecule agents by urine, drug inactivation by binding to proteins, and low stability of the drug in fluids.1212. S. Y. Wang, H. Z. Hu, X. C. Qing, Z. C. Zhang, and Z. W. Shao, “ Recent advances of drug delivery nanocarriers in osteosarcoma treatment,” J. Cancer 11(1), 69–82 (2020). https://doi.org/10.7150/jca.36588 Drug delivery and nanomedicine approaches play a pivotal role in modern medicine, ameliorating treatments of conventional drugs due to the ability to modulate the biodistribution and the target site accumulation of chemotherapeutic drugs, thereby reducing their toxicity.1313. E. Garbayo, S. Pascual-Gil, C. Rodríguez-Nogales, L. Saludas, A. Estella-Hermoso de Mendoza, and M. J. Blanco-Prieto, “ Nanomedicine and drug delivery systems in cancer and regenerative medicine,” Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 12(5), e1637 (2020). https://doi.org/10.1002/wnan.1637 There are several delivery systems for chemotherapeutic drugs that are applied in treating OS, some derived from cellular autocrine liposomal structures, others from synthetic liposomes or macromolecular proteins with or without a targeting ligand.1414. S. Wang, C. Chen, J. Wang, C.-B.-W. Li, J. Zhou, Y.-X. Liu, Y.-Q. Jiang, L. Zhu, C. Li, W. Gong, W. Guo, X. Tang, F.-Z. Yao, and K. Wang, “ Synergetic chemo-piezodynamic therapy of osteosarcoma enabled by defect-driven lead-free piezoelectrics,” Adv. Funct. Mater. 32(44), 2208128 (2022). https://doi.org/10.1002/adfm.202208128 We searched the keywords in databases to perform a co-occurrence analysis of OS and delivery systems, and the result illustrated in Fig. 1(a) shows that doxorubicin is the most commonly used chemotherapy drug for OS, and apoptosis and liposomes are also hot spots for research in the field. The result illustrated in Fig. 1(b) shows that in addition to doxorubicin and liposomes, cell survival and proliferation, combined modality therapy, chitosan, polyethylene glycols, cisplatin, and hydrogels, are recently being investigated in the area of anti-OS drug delivery. Here, we briefly summarize the advances and rationale in the area of chemotherapy drug delivery technologies for combating OS along with the specific challenges it may face.

TYPES OF NANOPARTICLES

Section:

ChooseTop of pageABSTRACTINTRODUCTIONTYPES OF NANOPARTICLES <<LIPOSOMESPROTEIN-BASED NANOPARTICL...EXOSOMESCARBON-BASED NANOCARRIERSOS-TARGETED DRUG DELIVERY...CELL MEMBRANE-BASED NANOP...STIMULI-RESPONSIVE NANOMA...CHALLENGES AND OUTLOOKNanosized drug delivery systems can be grossly classified into organic and inorganic carriers.88. Y. Liu, Q. Li, Q. Bai, and W. Jiang, “ Advances of smart nano-drug delivery systems in osteosarcoma treatment,” J. Mater. Chem. B 9(27), 5439–5450 (2021). https://doi.org/10.1039/D1TB00566A By exploiting of deep and comprehensive understanding of the cellular and molecular complexity of OS and the convenience of versatile materials, including natural materials, synthetic polymers, lipids, inorganic materials, and biomacromolecule scaffolds, the capability of drug delivery nanocarriers for delivering chemotherapeutics to tumor site has been enormously developed.1212. S. Y. Wang, H. Z. Hu, X. C. Qing, Z. C. Zhang, and Z. W. Shao, “ Recent advances of drug delivery nanocarriers in osteosarcoma treatment,” J. Cancer 11(1), 69–82 (2020). https://doi.org/10.7150/jca.36588 Currently, designed drug delivery systems are regularly nanocomposites composed of different types of materials because it is hard to acquire multifunctional nanocarriers from a single nanomaterial. Here, we present some drug delivery systems, combining controlled drug release properties, which can be triggered by various endogenous or exogenous stimulations, as illustrated in Fig. 2.

LIPOSOMES

Section:

ChooseTop of pageABSTRACTINTRODUCTIONTYPES OF NANOPARTICLESLIPOSOMES <<PROTEIN-BASED NANOPARTICL...EXOSOMESCARBON-BASED NANOCARRIERSOS-TARGETED DRUG DELIVERY...CELL MEMBRANE-BASED NANOP...STIMULI-RESPONSIVE NANOMA...CHALLENGES AND OUTLOOK

Liposomes are spherical vesicles formed by dispersing phospholipids in water, encapsulating part of the aqueous phase, with one or more concentric bilayers of phospholipids inside that allow the encapsulation of drugs with different solubility, ranging from 20 nm to several tens of micrometers in diameter. The physicochemical characteristics of the liposomes, such as surface charge, particle size, and stability, can be adapted to the phospholipid composition. The size, charge, and surface characteristics of liposomes can be easily manipulated by adding other components during the preparation of liposomes or before changing the preparation parameters, altering the half-life period and biodistribution pattern of the drug in the systemic circulation and, thus, improving its pharmacokinetic characteristics. The properties of liposomes make them an ideal delivery vehicle for chemotherapeutic drugs.

Doxil is the first anti-tumor liposome approved by the Food and Drug Administration (FDA) and has been found to have very different pharmacokinetic properties from doxorubicin in clinical trials.1616. Y. Barenholz, “ Doxil®–the first FDA-approved nano-drug: lessons learned,” J. Controlled Release 160(2), 117–134 (2012). https://doi.org/10.1016/j.jconrel.2012.03.020 The half-life of Doxil is approximately 90 h, whereas the initial distribution half-life of doxorubicin is only 5 min and the terminal half-life is 20–48 h. The area under the curve (AUC) of Doxil at a dose of 50 mg/m2 is 300-folds that of doxorubicin. Subsequent studies have shown that doxorubicin hydrochloride liposomes significantly enhance its bioavailability in tumors. Hu et al. developed a biomimetic hybrid nanocarrier loaded with doxorubicin in 2021 by combining liposomes with tumor-derived nanovesicles containing tumor antigens and endogenous danger signals, which can stimulate dendritic cell maturation and elicit subsequent antitumor immune responses for combinational immunochemotherapy.1717. M. Hu, J. Zhang, L. Kong, Y. Yu, Q. Hu, T. Yang, Y. Wang, K. Tu, Q. Qiao, X. Qin, and Z. Zhang, “ Immunogenic hybrid nanovesicles of liposomes and tumor-derived nanovesicles for cancer immunochemotherapy,” ACS Nano 15(2), 3123–3138 (2021). https://doi.org/10.1021/acsnano.0c09681 In this study, doxorubicin-loaded liposomes exhibited synergistic antitumor effects with promoted immunosuppressive effects on tumors and serve as an appealing chemotherapeutic drug delivery system. Similarly, Kleinerman et al. reported as early as 32 years ago on the use of monocyte activator muramyl tripeptide phosphatidylethanolamine to activate monocytes in vivo by liposome delivery to eradicate residual micrometastases after administration of adjuvant chemotherapy in children with OS.1818. E. S. Kleinerman, J. S. Snyder, and N. Jaffe, “ Influence of chemotherapy administration on monocyte activation by liposomal muramyl tripeptide phosphatidylethanolamine in children with osteosarcoma,” J. Clin. Oncol. 9(2), 259–267 (1991). https://doi.org/10.1200/JCO.1991.9.2.259 In combination with current research and clinical understanding, we may be able to combine these properties of liposomes to provide a more robust immune system and internal microenvironment containing well-functional tumoricidal immune cells for OS patients, along with immune-related therapeutic agents, such as IL-1, IL-6, and chemotherapeutic agents, to achieve complete tumor eradication.10,1910. C. Chen, L. Xie, T. Ren, Y. Huang, J. Xu, and W. Guo, “ Immunotherapy for osteosarcoma: Fundamental mechanism, rationale, and recent breakthroughs,” Cancer Lett. 500, 1–10 (2021). https://doi.org/10.1016/j.canlet.2020.12.02419. P. A. Meyers, “ Muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) in the treatment of osteosarcoma,” Adv. Exp. Med. Biol. 1257, 133–139 (2020). https://doi.org/10.1007/978-3-030-43032-0_11 The effects of liposome doxorubicin combined with ifosfamide on OS patients were evaluated by Huang et al., and the study demonstrated that liposome doxorubicin is exerted more powerful tumoricidal effects to extend overall survival and lower incidences of side effects than conventional doxorubicin plus ifosfamide.1717. M. Hu, J. Zhang, L. Kong, Y. Yu, Q. Hu, T. Yang, Y. Wang, K. Tu, Q. Qiao, X. Qin, and Z. Zhang, “ Immunogenic hybrid nanovesicles of liposomes and tumor-derived nanovesicles for cancer immunochemotherapy,” ACS Nano 15(2), 3123–3138 (2021). https://doi.org/10.1021/acsnano.0c09681 Meanwhile, the liposome delivery system also increased the levels of IFN-γ and IL-10 and reduced the expression of serum TSGF, VEGF, ERBB3, and TNF-α, which are closely associated with OS progression.However, liposome particles are easily phagocytosed by mononuclear macrophages and are unstable in vivo.2020. M. R. Villegas, A. Baeza, and M. Vallet-Regí, “ Nanotechnological strategies for protein delivery,” Molecules 23(5), 1008 (2018). https://doi.org/10.3390/molecules23051008 Despres et al. also reported that immune response can be activated by the surface charge of liposomes, which acts as an immune-activating function against tumors, but is also responsible for their destabilizing effects in vivo.2121. H. W. Despres, A. Sabra, P. Anderson, U. D. Hemraz, Y. Boluk, R. Sunasee, and K. Ckless, “ Mechanisms of the immune response cause by cationic and anionic surface functionalized cellulose nanocrystals using cell-based assays,” Toxicol. In Vitro 55, 124–133 (2019). https://doi.org/10.1016/j.tiv.2018.12.009 In numerous studies, polyethylene glycol (PEG) in this regard has been used to modify liposomes by steric hindrance stabilization for reducing particle aggregation, thus, enhancing the stability of liposomes in vivo, prolonging circulation time, and increasing targeted accumulation at tumor sites.2222. K. Wu, B. Yu, D. Li, Y. Tian, Y. Liu, and J. Jiang, “ Recent advances in nanoplatforms for the treatment of osteosarcoma,” Front. Oncol. 12, 805978 (2022). https://doi.org/10.3389/fonc.2022.805978 A phase I clinical trial of advanced OS reported in 2022 demonstrated that combination chemotherapy with pegylated liposomal doxorubicin plus cisplatin reduced cardiac toxicity of doxorubicin and gained an acceptable safety profile and promising clinical benefits.2323. X. Z. Wen, Q. Z. Pan, B. S. Xu, W. Xiao, D. S. Weng, J. J. Zhao, H. R. Xu, Z. Huang, X. H. Niu, and X. Zhang, “ Phase I study of pegylated liposomal doxorubicin and cisplatin in patients with advanced osteosarcoma,” Cancer Chemother. Pharmacol. 89(2), 209–215 (2022). https://doi.org/10.1007/s00280-021-04371-6 Despite promising advances in drug delivery, obstacles in balancing the high heterogeneity of OS with systemic circulatory stability are still present. The releases of stable dosage forms of drugs are relatively slow, and hydrophilic drug release is dependent on liposome degradation. Liposomal dosage forms of drugs offer longer systemic circulation time and minimal chemotherapeutic side effects, but at the expense of some efficacy. More studies are needed to strike a balance between obtaining consistently long circulation time and adequate drug release kinetics to achieve improved chemotherapeutic efficacy. Therefore, efforts to develop liposomes that actively trigger the release of chemotherapeutic drugs are of critical importance to advance the clinical application of drug delivery technologies.

PROTEIN-BASED NANOPARTICLES

Section:

ChooseTop of pageABSTRACTINTRODUCTIONTYPES OF NANOPARTICLESLIPOSOMESPROTEIN-BASED NANOPARTICL... <<EXOSOMESCARBON-BASED NANOCARRIERSOS-TARGETED DRUG DELIVERY...CELL MEMBRANE-BASED NANOP...STIMULI-RESPONSIVE NANOMA...CHALLENGES AND OUTLOOKSupramolecular nanodrug assembly driven by supramolecular chemistry is becoming an effective strategy for OS treatment. Wang et al. reported an engineered proteinaceous nanoensemble that can selectively functionalized as delivering payloads containing doxorubicin to OS cells, exerting a long-acting therapeutic efficacy on OS tumors and remarkable inhibition of pulmonary metastasis along with relieving doxorubicin cardiotoxicity.2424. S. Wang, B. Li, H. Zhang, J. Chen, X. Sun, J. Xu, T. Ren, Y. Zhang, C. Ma, W. Guo, and K. Liu, “ Improving bioavailability of hydrophobic prodrugs through supramolecular nanocarriers based on recombinant proteins for osteosarcoma treatment,” Angew. Chem., Int. Ed. 60(20), 11252–11256 (2021). https://doi.org/10.1002/anie.202101938 By using this nanocarriers based on recombinant proteins extremely prolonged the half-life profile of doxorubicin in nude mice model, and this slow release and targeting effects are both responsible for improving antitumor efficacy and reducing toxicity in vivo. Meng et al. demonstrated a synergistic therapy by combing chemotherapy with photothermal therapy through a bifunctional polydopamine-modified curcumin-loaded silk fibroin composite in treating OS.2525. Z. Meng, Y. Liu, K. Xu, X. Sun, Q. Yu, Z. Wu, and Z. Zhao, “ Biomimetic polydopamine-modified silk fibroin/curcumin nanofibrous scaffolds for chemo-photothermal therapy of bone tumor,” ACS Omega 6(34), 22213–22223 (2021). https://doi.org/10.1021/acsomega.1c02903 Researchers tested the curcumin loading and controlled release ability of the composite in this study, and the result showed its excellent photothermal properties and a typical pH- and near-infrared-controlled responsive behavior that can release drug rapidly for improving tumor permeation due to the weakly acidic microenvironment of OS and other solid tumors. Meanwhile, an effective inhibition effect on OS cells is also observed. There are obvious advantages of fibroin as a drug delivery system, such as property to controlling sustained drug release, improving drug solubility and stability, along with drug toxicity reduction. However, the problems including the slow degradation of fibroin in vivo and its immunogenicity targeted by immune systems remain to be solved.Similarly, an increasing number of protein-based carriers are being used in delivering chemotherapy drugs, such as lipoprotein, legumin, ferritin, and gelatin. Chen et al. designed an oleic acid-modified lipoprotein nanocarrier containing paclitaxel as a pH-sensitive targeting delivery system for tumor treatment.2626. C. Chen, H. Hu, M. Qiao, X. Zhao, Y. Wang, K. Chen, X. Guo, and D. Chen, “ Tumor-targeting and pH-sensitive lipoprotein-mimic nanocarrier for targeted intracellular delivery of paclitaxel,” Int. J. Pharm. 480(1–2), 116–127 (2015). https://doi.org/10.1016/j.ijpharm.2015.01.036 Lipoprotein nanocarrier showed non-cytotoxicity and pH-dependent drug release properties in vitro and targeting anti-tumor activity in tumor-bearing mice. The natural advantage of lipoprotein material, including naturally targeting property, biodegradability, biocompatibility, non-immunogenicity, and long circulation half-life, could be exploited in the future clinical drug treatment of OS. A doxorubicin gelatin microsphere and a doxorubicin polygelatin microsphere were reported in 2019 to be both effectively sustained releasing microspheres that anchored to D-periosteum for eradicating OS cells in vitro.2727. C. Chen, J. Dong, H. Chen, X. Wang, J. Mei, L. Wang, and C. J. Xian, “ Preparation of adriamycin gelatin microsphere-loaded decellularized periosteum that is cytotoxic to human osteosarcoma cells,” J. Cell. Physiol. 234(7), 10771–10781 (2019). https://doi.org/10.1002/jcp.27753 However, this kind of gelatin also has the drawbacks of rapid degradation and low mechanical strength, which needs to be optimized with the properties of other materials in future applications. Azarmi et al. established a matrix of parameters to synthesize gelatin-based nanoparticles with different sizes and a narrow size distribution to test the uptake of the nanoparticles by OS cells.2828. S. Azarmi, Y. Huang, H. Chen, S. McQuarrie, D. Abrams, W. Roa, W. H. Finlay, G. G. Miller, and R. Löbenberg, “ Optimization of a two-step desolvation method for preparing gelatin nanoparticles and cell uptake studies in 143B osteosarcoma cancer cells,” J. Pharm. Pharm. Sci. 9(1), 124–132 (2006). This study also provides theoretical and technical basis for the delivery of chemotherapeutic agents by gelatin-based carriers in OS.

EXOSOMES

Section:

ChooseTop of pageABSTRACTINTRODUCTIONTYPES OF NANOPARTICLESLIPOSOMESPROTEIN-BASED NANOPARTICL...EXOSOMES <<CARBON-BASED NANOCARRIERSOS-TARGETED DRUG DELIVERY...CELL MEMBRANE-BASED NANOP...STIMULI-RESPONSIVE NANOMA...CHALLENGES AND OUTLOOKIn 1983, Johnstone et al. first reported a membranous vesicle released by mature reticulocytes of sheep, which was initially thought to be a carrier of intracellular waste and unwanted proteins, such as transferrin receptors that enter the erythrocyte during maturation, and named the vesicle an exosome.2929. M. Colletti, A. Petretto, A. Galardi, V. Di Paolo, L. Tomao, C. Lavarello, E. Inglese, M. Bruschi, A. A. Lopez, L. Pascucci, B. Geoerger, H. Peinado, F. Locatelli, and A. Di Giannatale, “ Proteomic analysis of neuroblastoma-derived exosomes: New insights into a metastatic signature,” Proteomics 17, 1600430 (2017). https://doi.org/10.1002/pmic.201600430Exosomes are polycystic macrovesicles of size 40–100 nm in diameter, spontaneously produced and actively secreted by a variety of mammal cells. Exosomes have been recognized as important drug delivery systems and the most commonly used delivery system platform in recent years, carrying a variety of drugs and genetic information, such as proteins and nucleic acids, and travel freely between cell membranes with body fluids. Bone mesenchymal stem cells are frequently used for exosomes extraction in the field of bone tumors. Wang et al. used bone marrow mesenchymal stem cells (BM-MSCs) to generate exosomes by sequential extrusion, and successfully encapsulated doxorubicin by an ammonium sulfate gradient method to deliver doxorubicin in OS.3030. J. Wang, M. Li, L. Jin, P. Guo, Z. Zhang, C. Zhanghuang, X. Tan, T. Mi, J. Liu, X. Wu, G. Wei, and D. He, “ Exosome mimetics derived from bone marrow mesenchymal stem cells deliver doxorubicin to osteosarcoma in vitro and in vivo,” Drug Delivery 29(1), 3291–3303 (2022). https://doi.org/10.1080/10717544.2022.2141921 Similarly, Wei et al. used mesenchymal stem cell derived exosomes as doxorubicin carrier to treat OS, and result showed an obvious and safe curative effect compared to free doxorubicin.3131. H. Wei, F. Chen, J. Chen, H. Lin, S. Wang, Y. Wang, C. Wu, J. Lin, and G. Zhong, “ Mesenchymal stem cell derived exosomes as nanodrug carrier of doxorubicin for targeted osteosarcoma therapy via SDF1-CXCR4 axis,” Int. J. Nanomed. 17, 3483–3495 (2022). https://doi.org/10.2147/IJN.S372851 Figure 3 illustrated the antitumor activity, targeting capability, and mechanism of BM-MSC derived exosomes in OS. Additionally, exosomes from OS and other tumors are responsible for regulating cytokines, either the expression or secretion, and their signaling pathways that regulates tumor growth, angiogenesis, invasion, metastasis, and immune escape.3232. A. Santos, C. Domingues, I. Jarak, F. Veiga, and A. Figueiras, “ Osteosarcoma from the unknown to the use of exosomes as a versatile and dynamic therapeutic approach,” Eur. J. Pharm. Biopharm. 170, 91–111 (2022). https://doi.org/10.1016/j.ejpb.2021.12.003 These functions, which are essential for OS progression and are closely linked to exosomes, may in turn be exploited as targets by using exosomes to inhibit OS growth and metastasis and even drug resistance.3,333. C. Chen, Y. Guo, Q. Huang, B. Wang, W. Wang, J. Niu, J. Lou, J. Xu, T. Ren, Y. Huang, and W. Guo, “ PI3K inhibitor impairs tumor progression and enhances sensitivity to anlotinib in anlotinib-resistant osteosarcoma,” Cancer Lett. 536, 215660 (2022). https://doi.org/10.1016/j.canlet.2022.21566033. C. L. Chen, L. Zhang, Y. R. Jiao, Y. Zhou, Q. F. Ge, P. C. Li, X. J. Sun, and Z. Lv, “ miR-134 inhibits osteosarcoma cell invasion and metastasis through targeting MMP1 and MMP3 in vitro and in vivo,” FEBS Lett. 593(10), 1089–1101 (2019). https://doi.org/10.1002/1873-3468.13387

CARBON-BASED NANOCARRIERS

Section:

ChooseTop of pageABSTRACTINTRODUCTIONTYPES OF NANOPARTICLESLIPOSOMESPROTEIN-BASED NANOPARTICL...EXOSOMESCARBON-BASED NANOCARRIERS <<OS-TARGETED DRUG DELIVERY...CELL MEMBRANE-BASED NANOP...STIMULI-RESPONSIVE NANOMA...CHALLENGES AND OUTLOOKCarbon-based nanocarriers have excellent physicochemical properties including easily modified surfaces, excellent photo-thermal conversion ability, and high adsorption capacity. Ascribable to their merits, numerous carbon-based nanomaterials, such as carbon nanotubes, carbon dots, mesoporous carbon, and graphene oxide, have gained extensive attention and have witnessed a paradigm shift in tumor therapeutics in recent years.12,34,3512. S. Y. Wang, H. Z. Hu, X. C. Qing, Z. C. Zhang, and Z. W. Shao, “ Recent advances of drug delivery nanocarriers in osteosarcoma treatment,” J. Cancer 11(1), 69–82 (2020). https://doi.org/10.7150/jca.3658834. S. Augustine, J. Singh, M. Srivastava, M. Sharma, A. Das, and B. D. Malhotra, “ Recent advances in carbon based nanosystems for cancer theranostics,” Biomater. Sci. 5(5), 901–952 (2017). https://doi.org/10.1039/C7BM00008A35. H. Hassan, S. S. Diebold, L. A. Smyth, A. A. Walters, G. Lombardi, and K. T. Al-Jamal, “ Application of carbon nanotubes in cancer vaccines: Achievements, challenges and chances,” J. Controlled Release 297, 79–90 (2019). https://doi.org/10.1016/j.jconrel.2019.01.017 Augustine et al. blocked the TGFβ1-induced OS stem cell formation and the growth of tumors in vitro and in vivo by using single-walled carbon nanotube nanoparticles.3434. S. Augustine, J. Singh, M. Srivastava, M. Sharma, A. Das, and B. D. Malhotra, “ Recent advances in carbon based nanosystems for cancer theranostics,” Biomater. Sci. 5(5), 901–952 (2017). https://doi.org/10.1039/C7BM00008A OS stem cells tend to be resistant to chemotherapy and are closely associated with tumor metastasis, which is the most significant factor in the poor prognosis of OS. Therefore, carbon nanotube represented to be a promising agent for therapeutic applications in OS. Zhang et al. designed a carbon-based nanomaterial that increased the effective accumulation of doxorubicin in tumor cell nuclei and tissue and generated massive reactive oxygen species (ROS), thereby restraining tumor proliferation in nude mice model.3636. J. Zhang, C. Li, Q. Xue, X. Yin, Y. Li, W. He, X. Chen, J. Zhang, R. L. Reis, and Y. Wang, “ An efficient carbon-based drug delivery system for cancer therapy through the nucleus targeting and mitochondria mediated apoptotic pathway,” Small Methods 5(12), e2100539 (2021). https://doi.org/10.1002/smtd.202100539 Zero-dimensional carbon dots were applied in photothermal therapy under near-infrared irradiation and effectively inhibited OS tumor growth.3737. Y. Lu, L. Li, M. Li, Z. Lin, L. Wang, Y. Zhang, Q. Yin, H. Xia, and G. Han, “ Zero-dimensional carbon dots enhance bone regeneration, osteosarcoma ablation, and clinical bacterial eradication,” Bioconjugate Chem. 29(9), 2982–2993 (2018). https://doi.org/10.1021/acs.bioconjchem.8b00400 For the property of uncontrolled proliferation, tumor cells commonly have the ability to bypass the suicidal process that is a caspase-dependent form of programmed cell death called apoptosis under normal conditions.44. C. Chen, H. Zhang, Y. Yu, Q. Huang, W. Wang, J. Niu, J. Lou, T. Ren, Y. Huang, and W. Guo, “ Chloroquine suppresses proliferation and invasion and induces apoptosis of osteosarcoma cells associated with inhibition of phosphorylation of STAT3,” Aging 13(13), 17901–17913 (2021). https://doi.org/10.18632/aging.203196 Carbon dots was also found to induce the apoptosis of OS cells via the mitochondrial apoptotic signal, thereby inhibiting OS tumor growth and presenting cytotoxicity to 143B cell line.3838. Y. Jiao, Y. Guo, Y. Fan, R. Wang, X. Li, H. Wu, Z. Meng, X. Yang, Y. Cui, H. Liu, L. Pan, T. Maimaitijuma, J. Zhang, Y. Wang, Y. Cao, and T. Zhang, “ Triggering of apoptosis in osteosarcoma 143B cell line by carbon quantum dots via the mitochondrial apoptotic signal pathway,” BioMed Res. Int. 2020, 2846297. https://doi.org/10.1155/2020/2846297 The same functional capability was found in graphene oxide nanoparticles for inducing apoptosis in wild-type and CRISPR/Cas9-IGF/IGFBP3 knocked-out OS cells that used CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9) technology for gene-editing.3939. M. Burnett, Y. Abuetabh, A. Wronski, F. Shen, S. Persad, R. Leng, D. Eisenstat, and C. Sergi, “ Graphene oxide nanoparticles induce apoptosis in wild-type and CRISPR/Cas9-IGF/IGFBP3 knocked-out osteosarcoma cells,” J. Cancer 11(17), 5007–5023 (2020). https://doi.org/10.7150/jca.46464 In this study, Burnett et al. discovered that graphene oxide can produce ROS in tumor microenvironment (TME) in a time and concentration-dependent way, which has a significant cytotoxic effect against OS cells. Meanwhile, targeting the IGF1 and IGFBP3 signaling pathway was found to strengthen the cytotoxicity of graphene oxide for restraining tumor progression. However, to date, no studies have been reported on the combined use of graphene oxide and chemotherapeutic drugs in OS, which may be a research direction for the treatment of OS in the future.

OS-TARGETED DRUG DELIVERY SYSTEM

Section:

ChooseTop of pageABSTRACTINTRODUCTIONTYPES OF NANOPARTICLESLIPOSOMESPROTEIN-BASED NANOPARTICL...EXOSOMESCARBON-BASED NANOCARRIERSOS-TARGETED DRUG DELIVERY... <<CELL MEMBRANE-BASED NANOP...STIMULI-RESPONSIVE NANOMA...CHALLENGES AND OUTLOOKTargeted drug delivery in OS generally means precise delivery of the intravenously administered chemotherapeutic drugs to the target site by recognizing the properties of some OS or bone tissue. Therefore, it is important to identify the tissue characteristics of OS and find the suitable target for targeted drug delivery. Alendronate is usually used as a target to the bone tissue and is, thus, often seen in the treatment of OS. Morton et al. reported an approach that exploits the modularity of Layer-by-Layer (LbL) assembly to produce tissue-specific drug shippers for systemic administration in treating OS.4040. S. W. Morton, N. J. Shah, M. A. Quadir, Z. J. Deng, Z. Poon, and P. T. Hammond, “ Osteotropic therapy via targeted layer-by-layer nanoparticles,” Adv. Healthcare Mater. 3(6), 867–875 (2014). https://doi.org/10.1002/adhm.201300465 Because of the strong affinity for intraosseous hydroxyapatite, this alendronate-functionalized poly (acrylic acid) surface gives orthotropic liposome nanoparticles the property of bone targeting; thus, by active targeting of OS xenografts in nude mice with the LbL-targeted doxorubicin liposomes facilitates enhanced, prolonged tumor accumulation and dramatically improved efficacy. By combining with other targeting moieties, alendronate can also form a dual-targeted delivery system. Cluster of differentiation 44 (CD44) is a cell surface receptor highly expressed on OS cells and contributes to doxorubicin chemoresistance, which can be exploited for targeted chemotherapy of OS.4141. M. Gerardo-Ramírez, F. L. Keggenhoff, V. Giam, D. Becker, M. Groth, N. Hartmann, B. K. Straub, H. Morrison, P. R. Galle, J. U. Marquardt, P. Herrlich, and M. Hartmann, “ CD44 contributes to the regulation of MDR1 protein and doxorubicin chemoresistance in osteosarcoma,” Int. J. Mol. Sci. 23(15), 8616 (2022). https://doi.org/10.3390/ijms23158616 Feng et al. developed an efficient OS-targeting liposome system functionalized with a bone and CD44 dual-targeting polymer that conjugated alendronate with a ligand of CD44. Yin et al. reported polylactide nanoparticles coated with bone-seeking pamidronate for the targeted treatment of OS in dogs by loading with doxorubicin.4242. Q. Yin, L. Tang, K. Cai, R. Tong, R. Sternberg, X. Yang, L. W. Dobrucki, L. B. Borst, D. Kamstock, Z. Song, W. G. Helferich, J. Cheng, and T. M. Fan, “ Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis,” Proc. Natl. Acad. Sci. U. S. A. 113(32), E4601–E4609 (2016). https://doi.org/10.1073/pnas.1603316113 The neat thing about this study is that pamidronate can not only act as a bone-targeting agent to deliver doxorubicin better, but pamidronate itself also is one of the drugs used to treat OS. Therefore, this delivery system can kill two birds with one stone and greatly improve the treatment efficiency. At the same time, an increasing number of targets have been identified and applied for the targeted delivery of OS treatment, such as glucose, mannose, Arg-Gly-Asp, CD133 aptamers, and EGFR aptamers.43–4543. Z. Fang, Y. Sun, H. Xiao, P. Li, M. Liu, F. Ding, W. Kan, and R. Miao, “ Targeted osteosarcoma chemotherapy using RGD peptide-installed doxorubicin-loaded biodegradable polymeric micelle,” Biomed. Pharmacother. 85, 160–168 (2017). https://doi.org/10.1016/j.biopha.2016.11.13244. C. Liang, F. Li, L. Wang, Z. K. Zhang, C. Wang, B. He, J. Li, Z. Chen, A. B. Shaikh, J. Liu, X. Wu, S. Peng, L. Dang, B. Guo, X. He, D. W. T. Au, C. Lu, H. Zhu, B. T. Zhang, A. Lu, and G. Zhang, “ Tumor cell-targeted delivery of CRISPR/Cas9 by aptamer-functionalized lipopolymer for therapeutic genome editing of VEGFA in osteosarcoma,” Biomaterials 147, 68–85 (2017). https://doi.org/10.1016/j.biomaterials.2017.09.01545. K. Gui, X. Zhang, F. Chen, Z. Ge, S. Zhang, X. Qi, J. Sun, and Z. Yu, “ Lipid-polymer nanoparticles with CD133 aptamers for targeted delivery of all-trans retinoic acid to osteosarcoma initiating cells,” Biomed. Pharmacother. 111, 751–764 (2019). https://doi.org/10.1016/j.biopha.2018.11.118 The combination of these targets with different delivery materials in the future will bring more hope for the precise treatment of OS.

CELL MEMBRANE-BASED NANOPARTICLES

Section:

ChooseTop of pageABSTRACTINTRODUCTIONTYPES OF NANOPARTICLESLIPOSOMESPROTEIN-BASED NANOPARTICL...EXOSOMESCARBON-BASED NANOCARRIERSOS-TARGETED DRUG DELIVERY...CELL MEMBRANE-BASED NANOP... <<