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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
Osteosarcoma is a rare bone tumor that has a high incidence amongchildren and young adults. Despite recent therapeutic developments, osteosarcomastill presents major hurdles to achieving successful results, mainly due to thepresence of multi-drug-resistant cells.This monograph primarily aims to provide information about the basicscience behind the treatment of osteosarcoma along with experimental resultsfor a novel formulation that overcomes multidrug resistance, and therefore, mayserve as a viable treatment option. The book starts with an updated and conciseguide to the pathophysiology of the disease, while also introducing the readerto new therapies and materials (specifically chitosan, polyethyleneimine, poloxamers,poloxamines, and Pluronics®) used in the treatment process along with the aimsof the experiments present subsequently. Next, the book documents the materialsand methods used in developing polymeric micelles for delivering drugs toosteosarcoma sites. By explaining the basics of nanomedicine as a startingpoint, readers will understand how polymeric micelles act as facilitators ofdrug transport to cancer cells, and how one can synthesize a small stablemicelle (by creating derivatives of base nanomaterials), capable of activelytargeting osteosarcoma cells and overcoming multi-drug resistance. The chapterexplains the synthesis and characterization techniques of the materials used todevelop polymeric micelles.The results, a reflection of the conjugation of different experimentalsolutions initiated here, point to a modern route towards the search for a therapeutic solution for osteosarcoma.The simple, structured presentation coupled with relevant informationon the subject of micelle-based nanotherapeutic drug delivery make thismonograph an essential handbook for pharmaceutical scientists involved in thefield of nanomedicine, drug delivery, cancer therapy and any researchersassisting specialists in clinical oncology for the treatment of osteosarcoma.
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Veröffentlichungsjahr: 2022
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FOREWORD
Domingos de Carvalho FerreiraThe study presented here is primarily aimed at answering a fundamental question associated with the therapeutics of Osteosarcoma (OS). The proposed introduction of a novel formulation that overcomes multi-drug resistance as a viable treatment option.
Osteosarcoma is a rare bone tumor that has a high incidence among children and young adults. Despite therapeutic developments, OS still presents major barriers and resistance in terms of the success of the applied therapies, essentially due to the presence of multidrug-resistant cells.
In addition to an up-to-date and in-depth framework on the evolution of OS, this study also contextualizes the therapies within the evolving framework of the disease, as a backdrop and basis for the proposal of an innovative and more effective solution.
Taking nanomedicine as a starting point, and particularly polymeric micelles (PM) as facilitators of drug transport to cancer cells, the study proposes to obtain a small stable micelle, capable of actively targeting OS cells and overcoming multi-drug resistance.
The results, a reflection of the conjugation of different experimental solutions initiated here, point to a path and therapeutic solution for OS with consistent bases and a viable future contributing to a considerable evolutionary leap regarding possible therapeutics introduced in OS treatments.
PREFACE
Dr. Ana FigueirasOsteosarcoma (OS) is a rare and aggressive bone tumor that impacts mostly children and young adults. In spite of the numerous efforts made to date in the therapeutic field, OS still presents a low patient survival rate, high metastasis and relapse occurrence, mostly due to multidrug-resistant cells. To surpass that, nanomedicine has been extensively investigated for the targeted delivery of genetic material, drugs, or both. Polymeric micelles (PM) are nanosystems that facilitate the targeted transportation of poorly water-soluble drugs to cancer cells. These nanocomposites are composed of amphiphilic block copolymers, such as poloxamers, or Pluronics®, that self-assemble into a micellar structure when in contact with an aqueous solution. Pluronics® F68, and P123 are widely used poloxamers in the pharmaceutical area due to their advantageous characteristics. A micelleplex is formed from the conjugation of amphiphilic copolymer(s), a cationic polymer, linked to genetic material and/or drugs. This is because the cationic property will allow for the transportation of nucleic acids and thus, the possibility for dual therapy. Cationic polymers can be of natural or synthetic origin, such as chitosan or polyethyleneimine (PEI), respectively.
miRNAs have been implicated as participators in the development, metastasis and progression of OS. miRNA-145 is underexpressed in this disease and associated with a worse cancer prognosis. We hypothesize that the delivery of miRNA-145 to OS cells via a micelleplex, composed of Pluronic® F68 and either chitosan or PEI, will be able to inhibit tumor proliferation and migration.
In this work, we aim to elucidate the application of a micelleplex encapsulating miRNA-145 in order to achieve a targeted delivery to OS cells and overcome multidrug resistance, as a new and viable treatment option. As such, we have developed and optimized a mixed PM consisting of Pluronics® P123 and F68 complexed with PEI.
DISCLAIMER
This work was partially published in the following research paper:
Melim, C., Jarak, I., Veiga, F., Figueiras, A. The potential of micelleplexes as a therapeutic strategy for osteosarcoma disease. 3 Biotech10, 147 (2020). https://doi.org/10.1007/s13205-020-2142-5
FUNDING
This work received financial support from National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência) through project UIDB/50006/2020, co-financed by European Union (FEDER under the Partnership Agreement PT2020). It was also supported by the grant FCT PTDC/BTM-MAT/30255/2017 (POCI-01- 0145-FEDER-030255) from the Portuguese Foundation for Science and Technology (FCT) and the European Community Fund (FEDER) through the COMPETE2020 program.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENT
Declared none.
Abstract
Abstract
Osteosarcoma (OS) is a rare and aggressive bone tumor that impacts mostly children and young adults. In spite of the numerous efforts made to date in the therapeutic field, OS still presents a low patient survival rate, high metastasis and relapse occurrence, mostly due to multidrug resistant cells. To surpass that, nanomedicine has been extensively investigated for the targeted delivery of genetic material, drugs or both. Polymeric micelles (PM) are nanosystems that facilitate the targeted transportation of poorly water-soluble drugs to cancer cells. These nanocomposites are composed of amphiphilic block copolymers, such as poloxamers, or Pluronics®, that self-assemble into a micellar structure when in contact with an aqueous solution. Pluronics® F68, and P123 are widely used poloxamers in the pharmaceutical area due to their advantageous characteristics. A micelleplex is formed from the interactions of cationic amphiphilic copolymers with genetic material and/or drugs. Cationic components of micelleplexes can be of natural or synthetic origin, such as chitosan or polyethyleneimine (PEI), respectively.
miRNAs have been implicated as participators in the development, metastasis and progression of OS. miRNA-145 is underexpressed in this disease and associated with a worse cancer prognosis. We hypothesize that the delivery of miRNA-145 to OS cells via a micelleplex composed of Pluronic® F68 and either chitosan or PEI, will be able to inhibit tumor proliferation and migration.
In this work, we aim to elucidate the application of a micelleplex encapsulating miRNA-145 in order to achieve a targeted delivery to OS cells and overcome multidrug resistance, as a new and viable treatment option. As such, we have developed and optimized a mixed PM consisting of Pluronics® P123 and F68 and cationic graft copolymer F68-PEI.
Osteosarcoma (OS) is a rare and aggressive bone tumor that impacts mostly children and young adults. In spite of the numerous efforts made to date in the therapeutic field, OS still presents a low patient survival rate, high metastasis and relapse occurrence, mostly due to multidrug resistant cells. To surpass that, nanomedicine has been extensively investigated for the targeted delivery of genetic material, drugs or both. Polymeric micelles (PM) are nanosystems that facilitate the targeted transportation of poorly water-soluble drugs to cancer cells. These nanocomposites are composed of amphiphilic block copolymers, such as poloxamers, or Pluronics®, that self-assemble into a micellar structure when in contact with an aqueous solution. Pluronics® F68, and P123 are widely used poloxamers in the pharmaceutical area due to their advantageous characteristics. A micelleplex is formed from the interactions of cationic amphiphilic copolymers with genetic material and/or drugs. Cationic components of micelleplexes can be of natural or synthetic origin, such as chitosan or polyethyleneimine (PEI), respectively.
miRNAs have been implicated as participators in the development, metastasis and progression of OS. miRNA-145 is underexpressed in this disease and associated with a worse cancer prognosis. We hypothesize that the delivery of miRNA-145 to OS cells via a micelleplex composed of Pluronic® F68 and either chitosan or PEI, will be able to inhibit tumor proliferation and migration.
In this work, we aim to elucidate the application of a micelleplex encapsulating miRNA-145 in order to achieve a targeted delivery to OS cells and overcome multidrug resistance, as a new and viable treatment option. As such, we have developed and optimized a mixed PM consisting of Pluronics® P123 and F68 and cationic graft copolymer F68-PEI.
Keywords: Chitosan, Osteosarcoma, Micelleplex, miRNA-145, Pluronic® F68, Pluronic® P123, Polyethyleneimine, Polymeric Micelle.Introduction
1. Osteosarcoma
Osteosarcoma (OS) is a rare condition, with a yearly worldwide incidence of 3.4 per million people. It is, however, one of the most common cancers in adolescents, behind lymphoma and brain tumors (Misaghi et al., 2018). The defining feature that identifies the disease is the observation of osteoid matrix production by cancerous cells (Abarrategi et al., 2016). OS metastasis spreads via the hematogenous route in the same way as mesenchymal tumors and, typically, patients perish due to lung metastasis (Kansara & Thomas, 2007).
OS is characterized by a biphasic pattern, showing an incidence peak during adolescence and after the age of 60, with the first peak associated with the growth spurt during puberty. In addition, since OS development in adolescents mainly occurs in the more active areas of growth, a link between carcinogenesis and osteoblast activity was proposed (Fletcher et al., 2013; Kansara & Thomas, 2007). In the elderly population, the appearance of OS is of a secondary nature attributed to other diseases such as Paget’s disease of bone. In these patients, tumors develop in the axial part of the bone or in locations that were irradiated beforehand (Mirabello, Troisi & Savage, 2009).
OS’ patients often present swelling as well as pain in the metaphyseal bone of the distal femur, the proximal tibia, and proximal humerus. About 10% of cases involve the axial skeleton, mostly affecting the pelvis. Pain is mostly associated with the performance of active tasks and gradually starts appearing at rest (Cottrell, 2018; Ritter & Bielack, 2010). The pain’s onset is usually in adolescence and is associated with hospitalization, reduced survival, and poor quality of life of the patient (Smeester, Moriarity & Beitz, 2017).
In the past two decades, there has been little advancement regarding the prognosis of this disease, despite numerous research attempts. Children and adolescents present the worst prognostic. One of the most common problems of OS is the low patient survival rate, which has remained practically unchanged for 15 years, especially in those with metastatic tumors or in an advanced stage locally at the
time of diagnosis. Additionally, for those patients who experience disease relapse, treatment will depend on whether the tumor is removable, on the prior chemotherapy regimen and the time to relapse (O’Day & Gorlick, 2009). As it is assumed that changes in the current chemotherapy scenario will not provide an improvement in the OS landscape, there has been an increasing effort in the discovery of new therapeutic agents (Sampson et al., 2015).
According to the World Health Organization, the primary malignant bone tumor can be classified into seven types (see Table 1). In order to categorize the tumor, it is important to examine the microscopic, histological, and radiographic findings (Fletcher et al., 2013).
The tumor’s microenvironment (TME) is an essential feature to be regarded. In OS, the local TME has been linked to the induction and development of the disease, further contributing to a poor prognosis. Amid the non-tumor cells that compose the TME are mesenchymal stem cells, or MSCs. These non-hematopoietic precursor cells derived from the bone marrow are thought to be the origin of OS cells given the disease’s varied histological subtypes (Zheng et al., 2018). In fact, MSCs have the ability to self-differentiate and renew into multiple skeletal mesodermal lineages, including adipocytes, chondrocytes and osteoblasts (Tsukamoto et al., 2012). Tumor tissue MSCs, when recruited to the lesion, can obtain a cancer-associated fibroblast-like phenotype and promote tumor growth and progression (Bonuccelli et al., 2014; Zheng et al., 2018).
1.1. Pathophysiology
The majority of reported cases are sporadic in origin. OS develops in rapidly growing bones, preferentially during puberty and in the knee area (Choong et al., 2011). This disease is more prominent in males, with a male to female ratio of 1.5/1. Also, several environmental factors have been connected to the emergence of OS. UV light and ionizing radiation are the best described agents causative of OS. Exposure to radiation is responsible for 2% of the cases observed (Cottrell, 2018).
Chemical agents can be behind the development of OS. In 1938, Brunschwig injected 3-methylcholanthrene (MC) in mice, which resulted in the formation of an ossifying sarcoma in the tibia (Brunschwig, 1938). The combination of MC with chromium salts and the treatment with chromium compounds alone were explored regarding their ability to transform HOS TE85, a non-tumorigenic osteoblast-like human osteosarcoma cell line. The study was met with affirmative results, as both treatments lead to a higher anchorage-independent colony formation, more accentuated in the treatment including MC (Rani & Kumar, 1992). The potential hazards of beryllium exposure have been investigated for OS. In 1946, Gardner and Heslington injected several rabbits with zinc beryllium silicate and found the development of the disease in multiple regions (Kuschner, 1981). A similar study was also performed in rabbits focusing on beryllium oxide, with similar results indicating the formation of osteogenic sarcomas on two-thirds of the rabbits within a 16-month period (Dutra & Largent, 1950). Additionally, asbestos and aniline dyes have been linked to OS (Cottrell, 2018).
Viral infections have been associated with OS. Studies have demonstrated the implication of Simian virus 40 (SV40) as a possible tumor agent, however, the virus’ involvement in OS’s development was not proved. Instead, a human polyomavirus with similar properties to SV40 could be behind the obtained immunologic results (Mazzoni et al., 2015).
1.1.1. Genetic Alterations
Chromosomal abnormalities, mutations in tumor suppressor genes, or protooncogenes are the most common genetic causes of OS. Patients suffering from chromosomal and genetic diseases such as Bloom syndrome, Li-Fraumeni syndrome, and hereditary retinoblastoma are at risk of developing OS (Tan, Choong & Dass, 2009). Also, mutations in the RECQL4 have been identified in
several families suffering from Rothmund-Thomson syndrome (Fletcher et al., 2013). Furthermore, over 90% of documented high-grade cases demonstrate a tendency for aneuploidy, particularly a higher DNA content (hyperploidy) (Smeester, Moriarty & Beitz, 2017).
Genetic variations including chromosome losses on 3q, 6q, 9, 10, 13, 17p, and 18q or alternatively, gains in chromosomes 1p, 1q, 6p, 8q, and 17p are common in conventional OS. The genomic region that corresponds to a tumor suppressor gene will suffer a mutation or a deletion, but an oncogene region will experience an amplification or gain in function (Martin et al., 2012). Furthermore, the locus of cyclin-dependent kinase (CDK) inhibitors 2A, A2, and 2B are commonly affected, containing CDKN2A/p16INK4a, CDKNA2/p14ARF, and CDKN2B genes that, when mutated, may contribute to sporadic OS development (Kansara & Thomas, 2007; Mohseny et al., 2010).
Mutations in tumor suppressor genes p53 and Rb (retinoblastoma protein) lead to impairment of their protective function. Rb1 was the first tumor suppressor described and its loss of heterozygosity occurs in over 40% of cases. An alteration of the p53 loci shows tumorigenic properties with synergistic activity (Lindsey, Markel & Kleinerman, 2017). An amplification of the MDM2 (mouse double minute 2 homolog) gene, which codes for a p53 binding protein, and the c-myc protooncogene have also been reported in OS (Hong et al., 2015). In Table 2, proteins RB1, p53 and MDM2 are characterized according to their function and role in OS development.
The consequence of aberrant gene expression or epigenetic control of gene activity can reflect in the activity of various signaling pathways, and can create complex changes in molecular networks (Zucchini et al., 2019).
On the other hand, OS genotype presents a rapidly modifying nature, which in turn makes the study of potential genetic therapeutics a rather difficult task and also hinders the identification of a sole genetic cause (Martin et al., 2012; Mohseny et al., 2010).
1.2. Diagnosis and Treatment
Techniques currently used for diagnosis are varied and comprise both invasive and non-invasive methods. Non-invasive options include blood markers, such as alkaline phosphatase and lactose dehydrogenase, and imaging techniques like Magnetic Resonance Imaging (MRI), Computed Tomography (CT), Positron Emission Tomography (PET) and bone scintigraphy (Lindsey, Markel & Kleinerman, 2017). MRI is generally performed as first line, and it is applied to a lesion in order to ascertain if soft tissues or neovascular structures were harmed, the level of bone marrow that was replaced or if this tissue has extended into bordering joints. CT scans are also employed to determine cortical irregularities, fracture sites, mineralization of the bone, and implications of the neurovascular system. Even though it is a less sensitive modality than MRI for tumor location assessment, it is favored for lung metastasis. PET scan, used as a stand-alone or in combination with CT, is useful for determining the outcome of chemotherapy or to predict progression-free survival of the patient. Bone scintigraphy allows the detection of osseous metastasis. Invasive methods like bone biopsy and microscopic evaluation are still necessary practice to establish a definite diagnosis and determine a subtype classification and the patient’s response to neoadjuvant chemotherapy (Misaghi et al., 2018; Raimondi et al., 2017).
The standard treatment approach typically starts with 10 weeks of neoadjuvant chemotherapy, followed by surgery and 20 weeks of adjuvant chemotherapy. The most utilized antineoplastic agents are MAP (methotrexate, doxorubicin, cisplatin) (O’Day & Gorlick, 2009). In 2005, a randomized controlled trial, EURAMOS-1, was developed from a collaboration of four study groups in order to assess which patient treatment would exhibit the best results. Specifically, the addition of ifosfamide and etoposide to cisplatin, doxorubicin and methotrexate chemotherapy (MAPIE) to poor responders, or of pegylated interferon α (IFN-α) to MAP in good responders was examined. However, the trial was met with negative results, as MAPIE’s administration increased toxicity without improving event-free survival, while the addition of pegylated IFN-α did not perform better than MAP alone (Bielack et al., 2015; Marina et al., 2016).
Immunotherapy as a treatment option for OS is currently being heavily considered, following chemotherapy resistance. Vaccines, adoptive T-cell immunotherapy, inhibition of immune checkpoints, oncolytic viral therapy, immunomodulation and targeted therapies have been a target to research (Cottrell, 2018).
1.2.1. Targeted Therapy
Given the current limited therapeutic background for OS, targeted therapy has arisen as a promising alternative capable of improving antitumorigenic therapeutics. The introduction of molecular oncology has facilitated individualized patient care through the customization of the dose regimen, route of administration and selection of previously approved anticancer agents, as well as other new therapies (Ross, 2010). In this sense, the identification of molecular targets associated with OS development enables the use of nanotechnology-based drug delivery systems to such a target or biological pathway that, upon inactivation, will halt the progression of the disease (Alp et al., 2017).
Endoplasmic reticulum protein 29 (ERp29), highly regulated in primary OS cells, can be used as a prognostic biomarker and exhibits a protective role given the association between shorter patient survival and low ERp29 expression (Chaiyawat et al., 2019). Additionally, the PI3K-AKT-mTOR and EKR-MAPK pathways were also found to be upregulated, with the latter associated with tumorigenesis and stemness of the 3AB-OS cell line (Moriarity et al., 2015; Otoukesh et al., 2018).
Another biomarker that has been proposed is the antigen CD133+, which is expressed in cancer stem cells of bone sarcomas. These cells present stem cell-like properties such as a capacity for self-renewal, differentiation, proliferation and sphere formation. (Tirino et al., 2011). In a retrospective study, CD133+ cell expression was observed in about 60% of OS patients, with high expression levels correlating to distant metastasis (Xie et al., 2018).
In 2018, Zhang et al. proposed the inhibitor growth family of protein 5 (ING5) as a potential therapeutic target for OS. Identified as a tumor suppressor, its downregulation has been observed in several cancers, such as colorectal and breast cancer. The research group found that the protein was also downregulated in OS tumor cells when compared to normal tissues and identified a negative correlation between ING5 expression and tumor size and metastasis in the lung. In that sense, an overexpression of the protein caused apoptosis by activation of the Smad pathway and inhibited OS cell proliferation.
The IL-11 receptor α subunit (IL-11Rα) was shown to be associated with a poor prognosis in patients suffering from OS and was thus suggested as a cell surface marker for tumor progression. It was also shown that the expression of the receptor increases with metastatic progression and that both IL-11Rα and its ligand, IL-11, were upregulated in the human metastatic OS cell lines tested, KRIB, SJSA1 and LM7 (Lewis et al., 2017).
A recent study has implicated the secretory apolipoprotein J/clusterin (sCLU) as a potential therapeutic target for OS. The researchers found that this protein was overexpressed in the human OS cell line KHOS and that its targeted knockdown could increase tumor sensitivity towards chemotherapy and improve the prognosis of patients expressing high sCLU levels (Ma, Gao & Gao, 2019).
Semaphorin 4C, or SEMA4C, is an important axonal guidance regulator that has been implicated in OS development and metastasis. This protein’s expression was shown to be upregulated in OS tissue cells, and it promoted cellular transformation. Upon its knockdown, a reduction in OS proliferation and lung metastasis was observed, suggesting SEMA4C blockade therapy as a potential treatment option for metastatic OS (Smeester et al., 2019).
1.2. Challenges to Osteosarcoma Treatment
OS treatment has been met with several limitations over the years that have both impaired patient safety and stalled tumor eradication. The most common feature in patients suffering from metastatic OS is resistance to chemotherapy, as it is responsible for disease recurrence after a disease-free period, typically with a more aggressive tumor form or metastatic type, contributing to treatment failure (Phi et al., 2018; Posthuma De Boer, van Royen, & Helder, 2013). Moreover, the evident lack of therapeutic agents capable of performing a specific antitumor activity on the tumor site limits their efficiency, as the drug’s blood distribution is affected by several physiological responses or barriers, so the therapeutic dosage administered is lowered in order to avoid considerable cytotoxicity to normal cells. (Wang et al., 2020). Since these problems and others, which include poor drug pharmacokinetics, high cellular toxicity, and drug resistance, are still present in the panorama of OS, several nanomedicine-based studies have been conducted aiming to overcome these challenges (Savvidou et al., 2016).
Nanomedicine refers to the use of materials of nanometric size for therapeutic and imaging purposes, for instance, when it comes to the diagnosis, monitoring and treatment of cancer. Currently, a large number of nano-delivery systems are being studied for cancer treatment, such as liposomes, polymeric micelles (PM), metallic nanoparticles, solid lipid nanoparticles, dendrimers or albumin nanoparticles (Chow & Ho, 2013; Tong & Kohane, 2016). These nanocarriers present beneficial characteristics capable of improving the therapeutic efficacy of anticancer drugs. These include their potential to modulate a drug’s pharmacokinetic profile and tissue distribution for a preferred tumor site accumulation, increased in vivo stability leading to an extended blood circulation half-life, and controlled release (Wicki et al., 2015). Furthermore, the coupling of surface ligands to the nanoparticles and the development of stimuli-responsive nanosystems allow for active targeting and controlled drug release. These properties cause a decrease in the toxicity of drugs and thus an improvement in the patient’s safety (Rodríguez-Nogales et al., 2018; Shi et al., 2017).
