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 Table of Contents  
Year : 2016  |  Volume : 2  |  Issue : 5  |  Page : 154-161

Nanoparticle drug delivery systems and three-dimensional cell cultures in cancer treatments and research

1 Key Laboratory of Bio resource and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, Sichuan, China
2 Tissue Engineering Labs, VA Boston Healthcare System, Boston, MA; Department of Orthopedics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Date of Submission19-Apr-2016
Date of Acceptance20-Aug-2016
Date of Web Publication24-Oct-2016

Correspondence Address:
Dr. Wanting Niu
Department of Orthopedics, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2395-3977.192933

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Being a great threat to human health, with no permanent cure yet, better treatment and further research in cancer are inevitable. Nanoparticle drug delivery systems (NDDSs), especially pH-sensitive NDDSs, such as lipid-based, polymeric, and mesoporous silica nanoparticles have played a significant role in cancer treatments. Further, three-dimensional (3D) cell cultures models, which include tumor spheroid models, microfluidic systems, and matrix/scaffolds-based 3D tumor, better mimic the tumor microenvironment than the conventional two-dimensional cultures, making it possible to better understand the disease while serving as a useful in vitro model for future research. The present review mainly focuses on such 3D cell cultures and drug delivery systems that are applied in cancer research and treatments.

Keywords: Cancer research and treatments, nanoparticle drug delivery systems, three-dimensional cell cultures, tissue engineering techniques

How to cite this article:
Shi W, Weng D, Niu W. Nanoparticle drug delivery systems and three-dimensional cell cultures in cancer treatments and research. Cancer Transl Med 2016;2:154-61

How to cite this URL:
Shi W, Weng D, Niu W. Nanoparticle drug delivery systems and three-dimensional cell cultures in cancer treatments and research. Cancer Transl Med [serial online] 2016 [cited 2019 Dec 11];2:154-61. Available from: http://www.cancertm.com/text.asp?2016/2/5/154/192933

  Introduction Top

It has been reported that malignant tumors are the leading cause of death worldwide, accounting for about 25% in the US alone.[1] Hence, it is crucial to improve the efficacy of drug delivery systems in cancer, which itself poses a big challenge. Currently, there are many anticancer drugs showing feeble effects on the treatment of solid tumors because of the characteristics of tumor microenvironments. Hence, it is important to develop effective drug delivery systems to improve the effectiveness of such anticancer drugs. Early nanoparticle (NP)-based drug delivery systems, such as polymeric NPs reported in 1979,[2] are shown to improve the efficacy of the drug, which have been applied in the cancer treatments for a long time.

In terms of evaluating the efficacy of drug delivery systems, the three-dimensional (3D) cell culture models which mimic the native complex tumor microenvironment in vitro have been studied for a long time.[3],[4],[5],[6] In 1970, Sutherland et al.[7] developed a spheroid cell culture system. In 1986, Kleinman et al.,[8] for the first time, illustrated the basement membrane activity from mouse tumor in cell cultures. In 1994, researchers tried to understand the 3D cell culture models and the impact of growth factors on them.[9] In addition, 3D cell cultures serve better models than conventional two-dimensional (2D) cell cultures, in diagnostic, pathogenesis, and drug discovery studies.

  Nanoparticle Drug Delivery System Top

There are many anticancer drugs showing feeble effects on the treatment of solid tumors, such as taxanes.[10] The blood vessels supplying the tumors, due to their increased rate of proliferation, travel long distances from the parent vessels than found in normal tissues to reach the normal site. This reduces the efficacy of many traditional anticancer drugs to reach the tumor because of their lower penetrating abilities.[11],[12] To overcome this disadvantage, nanoparticle drug delivery systems (NDDSs) are introduced, which are discussed below.

NDDS have been widely applied in the field of cancer therapy since two decades[13] while it was introduced to pharmacology back in 1970s.[14] NP size ranges from 1 to 100 nm in general. Moreover, NPs in tiny sizes cause toxicities for organisms. They can accumulate in kidney, liver, and even brain due to the possibility of passing through the blood-brain barrier.[15] Apart from the surface area, composition and charge of NPs can also cause undesired toxicities, which can be reduced or avoided by masking the NPs and adding targeting moieties to the NPs.[16] NDDS includes polymeric NPs, lipid-based carriers, mesoporous silica nanoparticles (MSNs),[17] dendrimers, carbon nanotubes, and metal-based NPs which are advantageous in drug distribution compared with conventional drug delivery systems.[14] In addition, NDDS, compared to conventional drug delivery systems, can prevent the degradation of the drug from increasing its local concentration and control the releasing time.[14] Furthermore, NDDS reduces immunogenicity, increases bioavailability and solubility of drugs, modifies pharmacokinetics, and improves the half-life of the drug.[18] Cancer drug delivery systems require precision targeting ability so that the drug can be targeted specifically to the tumor tissue, thereby minimizing its adverse effects on the adjacent healthy tissue.

Lipid-based, polymeric, and mesoporous silica nanoparticle drug delivery system

Lipid-based NDDSs have various types, such as liposomes, micelles, nano-(micro) emulsions, and solid lipid NPs. Among these, liposome NPs have been approved by the food and drug administration for their application in cancer therapies.[13] Parhi and Sahoo[19] formulated a multifunctional nanotheranostic system for breast cancer therapy and imaging based on glyceryl monooleate lipid NPs. The trastuzumab (Tmab), a humanized monoclonal antibody, was conjugated to the surface of NPs to target human epidermal growth factor receptor-2 (Her-2) positive breast cancer cells, whereas the anticancer drug rapamycin (rapa) and imaging agent (quantum dots, QDs) were embedded inside the lipid NPs. When the Tmab-QDs-rapa-NPs combined with Her-2 receptors on the cancer cell surface, they could enter the cell through receptor-mediated endocytosis. This system was tested effective on Her-2 positive SKBR 3 breast cancer cell line both in monolayer and 3D tumor spheroid models.[20] It is reported that lipid-based NPs contribute to the treatment of various EGFR positive cancers.[19]

Polymeric NDDSs are extremely common materials of nanoscale drug delivery systems; the earliest cancer therapy application was reported in 1979.[2] Some tumor cells and tumor endothelial cells express CD13, which also behaves as a receptor of Asn-Gly-Arg (NGR) motifs containing peptide. Gupta et al.[21] conjugated cyclic NGR on the polyethylene glycol (PEG) end of poly (D, L-lactic-co-glycolic acid) (PLGA)-PEG copolymer, then encapsulated docetaxel, a potent anticancer moiety by emulsion/solvent evaporation method to form therapeutic NPs. The in vitro results showed that cNGR-functionalized PEG-PLGA-NPs can strengthen the efficacy of antitumor drug delivery tested cytotoxicity, cell apoptosis, and cell cycle analysis.[21] Another study reported that when beclin1 self-assembled into poly(β-amino ester) micelles, the formed NPs could enhance cytotoxicity to MCF-7 breast cancer cells through the induction of autophagy. Compared to unshelled small molecule drugs, the polymer encapsulated beclin1 was more stable, more specific in targetin, and thus had elevated delivery efficiency to tumors tissues.[22]

Mesoporous silica NDDSs have attracted much attention in the application of cancer therapies due to their microstructure and high-specific surface area. The first mesoporous silica NDDS, MCM-41 type MSNs, was reported in 2001.[17],[23] Hanafi-Bojd et al.[24] showed that epirubicin hydrochloride carried by functionalized MSNs was more effective than free epirubicin hydrochloride on a C-26 colon carcinoma model.[24] Cheng et al.[25] encapsulated anticancer drug doxorubicin (DOX) in MSNs then sealed the surface pores of MSNs with tumor-targeting cellular membrane-penetrating peptides and mitochondria-targeting therapeutic peptides (TPP) through sulfide bonds. These trifunctional NPs could enter cells as endosomes and then release TPP and DOX in cytoplasm. This novel design promoted NPDDSs for synergistic cancer therapy.[25]

In general, polymeric NDDSs can provide more versatile structures than lipid-based NDDSs[13] while mesoporous silica NDDSs are more flexible and versatile than polymeric NDDSs and lipid-based NDDSs.[17] Both lipid-based NDDSs and mesoporous silica NDDSs have more suitable and lower cost scale-up production methods than polymeric NDDSs.[13],[17] In the aspect of in vivo stability, mesoporous silica NDDSs and polymeric NDDSs are more stable compared with lipid-based NDDSs. In terms of toxicity, polymeric NDDSs have the highest toxicity among the three mentioned NDDSs, especially the poly(lactic acid) (PLA) and PLGA-based NPs.[26]

Drug delivery systems based on biodegradable and biocompatible polymers are the most successful ones of sustained drug release for brain cancer.[27] The most common NPs contain polymeric drug micelles and liposomes in the treatments of breast cancer.[28] Meanwhile, NDDSs play an important role in the treatment of myeloma. For example, the NPs containing PLGA, PEG, and bisphosphonate effectively inhibit myeloma progression as drug delivery system, which solves the difficulty of drug off-target and low drug concentrations in tumor.[29]

pH-sensitive nanoparticle drug delivery systems

NDDSs, which can respond to stimuli, have properties that can steer away from biological barriers and deliver anticancer drugs to tumor cells of target. There are various stimuli existing in human bodies, biological stimuli such as enzymes[30] and glucose,[31] chemical stimuli such as pH[32] and ionic[33] , and physical stimuli such as temperature[34] and electricity.[35] Moreover, NDDSs capable of responding to these stimuli have been developed to effectively delivery anticancer drugs. Among the different types of stimulus mentioned above, pH-sensitive NDDSs have been widely used to design sensitive nanosystems for drug delivery in cancer therapy, which have been approved by the food and drug administration (FDA).[36] Such NDDSs can be released in the acidic microenvironment and hence are more advantageous to human because the tumor microenvironment is more acidic than the normal microenvironment. Apart from that, as a result of abnormal active metabolism, the pH of the tumor microenvironment is around 5.7-5.8 whereas the pH of normal microenvironment is about 7.4 [Figure 1]a. pH-sensitive NDDSs can be obtained in some ways. One of them is using acid-labile chemical bonds to covalently attach drug molecules onto the surfaces of nanocarriers. Acetal, orthoester, hydrazone, imine, and cis-aconyl bonds are the acid-labile linkers, which are stable at neutral pH but are hydrolyzed or degraded in acidic microenvironment [Figure 1]b.[37] Importing ionizable chemical groups is another method to obtain pH-sensitive NDDSs. Amines, phosphoric acids, and carboxylic acids are ionizable chemical groups and they can accept or release protons in response to changes in the pH of the environment to release the drug.[38] Incorporating carbon dioxide-generating precursors to NPs can also produce pH-sensitive NDDSs.[39] Sodium bicarbonate[40] and ammonium bicarbonate[39] can generate CO2 .[36]
Figure 1. Schematic illustration of drugs released from acid-labile chemical bond-based nanoparticle drug delivery systems. (a) Acid-labile chemical bond-based nanoparticle drug delivery systems would not release the drug in the blood vessel since its pH is about 7.4. In contrast, they release the anticancer drug in the tumor tissues where the pH is about 5.7. (b) In acid-labile chemical bond-based nanoparticle drug delivery systems, drugs are conjugated to nanocarriers by acid-labile chemical bonds. When pH decreases from 7.4 to 5.7, the acid-labile chemical bonds break and release the drug

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It is a promising strategy that pH-sensitive NDDSs are associated with lipid-based,[41],[42] polymeric,[43],[44],[45],[46] and MSNs.[47],[48],[49] It has been reported that pH-sensitive lipoprotein-mimic nanocarriers are highly effective in targeting tumors for delivering paclitaxel.[41] pH-sensitive polymeric NPs were also used to deliver doxorubicin to overcome its severe side effects.[43] Moreira et al.[47] showed that pH-responsive MSN with a calcium carbonate-based coating is an effective strategy to deliver the drug.

  Three-Dimensional Cell Cultures Top

Three-dimensional vs. two-dimensional cell cultures

Although 2D cell cultures can explain some cancer cell behaviors and related hypothetical mechanisms,[50] 3D tumor cell cultures in vitro better mimic the native and complex tumor microenvironment, gene expression profiles, cellular signaling pathways,[51] and the interactions between cell-cell and cell-extracellular matrix (ECM).[50] It has been reported that hypoxia was only observed in the dense 3D multicellular spheroids,[52] which has not been observed in 2D cell cultures. Therefore, 3D cell cultures better mimic the hypoxia condition of breast cancer compared to 2D cell cultures. In addition, outcomes of some studies using 2D vs. 3D cell cultures are different. For example, as reported by Colley et al.,[53] to damage head and neck squamous cell carcinoma cells, it is required to deliver the drugs deep into the center of the spheroid in 3D tumor models while only a short contact was required in 2D monolayer cultures. Sprague et al.[54] reported that dendritic cells can mimic the microenvironments of ovarian and breast cancer in 3D cell cultures through their interaction with collagen proteins but not in 2D cell cultures. Furthermore, 3D in vitro models have many advantages compared with animal models for cancer researches including immunodeficient mice, chemical carcinogenesis mouse model, and radiation carcinogenesis mouse model that are complex, unpredictable, and have ethical issues.[50] For instance, Zheng et al.[55] created a novel human gastric tissue-derived orthotopic and metastatic mouse model of human gastric cancer, but after human gastric tissue was implanted, its normal function in mouse was difficult to achieve. Therefore, 3D cell cultures are widely applied in a variety of fields in cancer research, including diagnostic and therapeutic application, pathogenesis study, drug testing,[56] and drug discovery.[57]

In vitro three-dimensional cancer models

In vitro 3D cancer models can be classified into spheroids in suspension, microfluidic systems, gel embedding, scaffold-based models, and cell printing.[50] Kimlin et al.[58] classified 3D culture models into cells cultured as multicellular aggregates, cells cultured on inserts, and cells embedded in matrices. Here, we detail in vitro 3D cancer models including multicellular tumor spheroid model, microfluidic system, matrix/scaffold-derived 3D tumor model, and scaffold-based model [Table 1].
Table 1. The advantages of three in vitro three-dimensional cancer models

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Tumor spheroid

Tumor spheroids are masses of polymeric cells to simulate the characteristics of tumors in vitro.[59] The tumor spheroids can be formed in a few ways such as liquid overlay, spinner flasks, gyratory rotation systems, hanging drop, and suspension cultures.[60] The multicellular tumor spheroid models are widely applied in oncology. Moreover, the multicellular tumor spheroid with fluorescent readouts and high-content imaging are effective to improve the potential of antidrug discovery and the accuracy of high-throughput screenings.[61]

There are some experiments that compare multicellular 3D tumor spheroid models and 2D monolayer cultures which demonstrate that the former is advantageous for its similarity to the in vivo tumor microenvironment and other aspects.[62],[63],[64] Terashima et al.[65] compared the regulations of the expression of genes encoding the drug-metabolizing enzymes CYP1A1 and CYP1A2 in the human hepatocellular carcinoma cells in 3D tumor spheroids and 2D monolayer cultures and found that the expression of CYP1A1 and CYP1A2 in the 3D tumor spheroids was higher than that in 2D cultured cells.

The tumor spheroid model is appropriate in the investigation of different types of tumors such as brain tumors,[66] ovarian cancer,[67] and lung cancer.[63] Vinci et al.[66] developed an invasion assay method to use 3D tumor spheroids in a human glioblastoma cell line. These 3D tumor spheroids can better simulate the invasion of some cancers in vitro, especially brain tumors and squamous cell carcinoma of the head and neck without distant metastases.[66] Similarly, Raghavan et al.[67] developed 3D ovarian cancer spheroids using hanging drop arrays, whose advantage was the need of very small number of ovarian cancer cells at the initiation. The multicellular tumor spheroid model was used to estimate the rate of oxygen consumption.[67] In addition, this system has been used for ovarian cancer spheroid biology researches and preclinical drug sensitivity assays.[67] Multicellular tumor spheroids are also applied in anti-lung cancer drug testing.[64]

Microfluidic systems

Microfluidic systems have been developed rapidly since microfluidics emerged as a tool in biological research in the early 1990s.[68] The systems are designed to handle fluids in microchannels, with size ranging from 1 to 1000 μm.[69] Microfluidic systems have many advantages to become a valuable tool for diagnosing and investigating cancer, including small amount of samples and reagents consumption, intensive spatio-temporal control, high sensitivity, and high throughput.[68],[69] In addition, the microfluidic system can be applied in quantitative detection of mutations,[70] drug testing,[71],[72] and high-throughput screening of anticancer drugs.[73],[74]

As the microfluidic systems work at the microlevel, they are capable of simultaneously handling a large quantity of sample and hence provide high throughput. Xu et al.[75] created a microfluidic chip-based 3D coculture system to form a valid drug sensitivity test platform. On this platform, sensitivities of many anticancer drugs were tested at the same time, and finally, the precise doses of anticancer drugs were screened, and individualized treatments were designed for eight patients with lung cancer.[75] A patient-specific 3D microfluidic system was used to mimic the dynamic physiological microenvironment in bone marrow, assess drugs, investigate multiple myeloma, and evaluate individualized treatments for multiple myeloma patients.[76] Analogously, Bruce et al.[77] used 3D microfluidic triculture model to simulate the bone marrow microenvironment to investigate acute lymphoblastic leukemia.

Matrix/scaffold-based three-dimensional tumor models

Matrix-based 3D tumor models are needed because the biochemical, mechanical, and architectural properties of the ECM play a critical role in cancer progression.[78] With the development of tissue engineering, matrix/scaffold-based 3D tumor models are created to better understand the dynamic interactions between the solid tumors and their surrounding microenvironments, especially the natural ECMs [Table 2].[61],[79]
Table 2. The advantages of materials used in matrix/scaffold-based three-dimensional tumor models

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Basement membrane extractions, collagen type I, silk fibroin biomaterial, alginates, and hyaluronic acid (HA) all belong to naturally derived matrices, with which tumor cells can interact and thus simulate tumor microenvironment.[59] The basement membrane is associated with many tissues, which can be used to investigate differentiation, apoptosis, cancer growth, invasion, and angiogenesis. Moreover, basement membrane can be applied in various cancer investigations, such as breast cancer,[80],[81] ovarian cancer,[82] and endometrial cancer.[83] When breast cancer cells were cultured on basement membrane protein matrices, the cell invasion into the surrounding environment and correlative mechanisms can be identified.[80] The constituents of Matrigel are similar to that of other basement membrane proteins including laminins, collagen IV, entactin, heparan sulfate proteoglycan, or non-ECM proteins.[84] Matrigel is widely used in cancer investigations, such as breast tumor,[85],[86],[87] colorectal cancer,[88],[89] and lung cancer,[90] study of tumor colony formation, tumor cell metastasis, tumor-normal cell interaction,[88] and detection of invasion kinetics of individual cells.[90]

Type I collagen has also been applied in 3D cancer models.[91] Magdeldin et al.[92] produced a colorectal cancer model with collagen type I hydrogels, which was used as an in vitro drug screening platform to observe the morphology of colorectal cancer cells and test the efficacy of Cetuximab on HT29 and HCT116 cell lines.[92] Compared with basement membrane extractions, type I collagen has an advantage of manufacturing reproducibility. In addition, basement membrane extractions have residual growth factors and undefined components. However, Type I collagen is sensitive to temperature, pH, and ionic concentrations, which lead to different results from different laboratories.[79]

In comparison to the two types of naturally derived matrices described above, silk fibroin biomaterials have more advantages due to their particular mechanical properties, good biocompatibility, and degradability that can be easily controlled, which make silk fibroin biomaterials widely used in the field of tissue regenerations, such as vascular regeneration, neural tissue repair, skin reconstruction, and musculoskeletal tissue reformation.[93]

Alginate and HA are also naturally derived matrices broadly used in constructing 3D cell culture systems. Alginates could be used as biodegradable hydrogels with controlled mechanical properties and pore sizes,[59] which can be applied in screening anticancer drugs of nonsmall cell lung cancer,[94] real-time monitoring of cell proliferation and apoptosis,[95] and characterization of human head and neck squamous cell carcinoma.[96] Alginates do not involve in cancer growth and progression, which are observed with HA.[97] HA is a simple linear polysaccharide interacting with proteins and proteoglycans, such as cell surface receptors, which regulate tumor progression and metastasis.[97] Therefore, HA hydrogels are applied in tumor progression and metastasis investigations, especially for HA-rich connective tissue models. With the purpose of studying HA interactive proteins in prostate cancer (PCa) motility, invasive PCa cells were seeded in HA hydrogels to form "invadopodia." The number of invadopodia, cluster size, and morphology, as well as convergence, provide quantitative parameters for evaluating invasive potential.[98] In another study, human renal cell carcinoma subline, 786-O cells survived longer but with lower proliferation rate in HA gels compared to its counterpart 2D cultures. Importantly, some adhesion-related molecules, angiogenesis factors, and osteolytic factors which are related to bone metastasis were found upregulated compared to the 2D cultures.[99]

The development of synthetic matrices and scaffolds also helps to stimulate critical characteristics of ECMs such as matrix morphology and porosity, which are significantly involved in burgeoning approaches in tissue engineering.[79] Moreover, compared with natural polymers, synthetic matrices provide controlled conditions due to their designed biochemical, mechanical, and degradable properties. There are various synthetic matrices and scaffolds, such as polyacrylamide hydrogel, PLA, poly(glycolic acid) (PGA), PLGA, and PEG porous scaffolds.[78]

Although polyacrylamide hydrogel contributes to cancer investigation, its usage in 3D culture studies is limited due to its cytotoxicity while PLA and PGA have better cell compatibility and hence have been broadly applied in 3D cell cultures.[100] Porous scaffolds are also widely applied in tissue engineering. PEG could easily form a 3D polymeric network and its swelling degree could be adjusted under physiological conditions.[79] In addition, PEG is an FDA-approved hydrophilic polymer widely studied both in vitro and in vivo.[100]

  Conclusion and Future Perspectives Top

Drug delivery system, especially implantable biodegradable DDS and NDDSs, plays a crucial role in the treatment of cancer. Among NDDSs, pH-responsive NDDSs have been most widely used to design sensitive nanosystems for drug delivery in cancer therapy, which have been approved by the FDA. NPs contain various kinds of materials, such as lipid-based, polymeric, and mesoporous silica NDDS which have different characteristics. Excitingly, cancer immunotherapy drugs formulated using NPs are more efficient than the original drugs.[101] Therefore, NDDSs can be used to enhance the efficacy of cancer immunotherapies.

3D cell cultures have many advantages over 2D cell cultures and animal models. They mimic the native complex tumor microenvironments and other aspects and thus are widely applied in the field of cancer therapeutics, which include tumor spheroid models, microfluidic systems, and matrix/scaffold-based 3D tumor models. Recent clinical trials have shown that cancer immunotherapies, e.g. checkpoint blockade antibodies, are beneficial and efficacious in cancer treatments.[102],[103] Because of their advantages, 3D cell cultures are increasingly being applied for the evaluation of new therapies, especially cancer immunotherapies.[104] Microfluidic systems can also be used in the evaluation of individualized cancer therapies, such as cancer immunotherapies using cells or tissues from patients.[75]

Notably, to fully develop reliable 3D tumor models for drug discovery, screening, and testing, some disease-specific factors need to be evaluated further and optimized in large-scale studies.[103] Although the interaction between cancer and stromal cells is essential for tumorigenesis and progression, cells of the innate, and adaptive immune system can enhance the processes, which include monocytes, macrophages, dendritic cells, neutrophils, and lymphocytes. Moreover, in recent years, cancer immune microenvironment has been shown to play a major role in tumorigenesis, development, and metastasis. Therefore, 3D models should elucidate and simulate these interactions in vitro. It is a challenge to engineer immunocompetent 3D cancer systems.[105] To understand the differences of employing different cell lines and primary cells in the same study is another challenging field.

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