Deep Penetration of Nanoparticulate Drug Delivery Systems into Tumors: Challenges and Solutions

Li, L; Sun, Jing; He, Zhilong

doi:10.2174/09298673113209990004

Cited by 42 publications

(39 citation statements)

References 11 publications

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“…9 The result is that drugs localize in regions proximal to blood vessels, leaving distal regions of the tumor untreated. 10,11 Therefore, although oligonucleotide delivery systems can concentrate in the tumor, there may not be sufficient penetration and distribution throughout the tissue to produce a therapeutic effect.…”

Section: Introductionmentioning

confidence: 99%

“…Even though poor penetration into tumors may be a contributing factor to inadequate therapeutic effects of nanoparticle delivery systems, 10 such systems are commonly tested in vitro using monolayer cultures where penetration is unnecessary. Cells grown in two dimensions lack many of the characteristics of those found in tumors, including a nutritional gradient, a complex microenvironment, and an altered genetic profile.…”

Section: Introductionmentioning

confidence: 99%

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Multicellular Tumor Spheroids as a Model for Assessing Delivery of Oligonucleotides in Three Dimensions

Carver

Xin

Juliano

2014

Molecular Therapy - Nucleic Acids

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Oligonucleotides have shown promise in selectively manipulating gene expression in vitro, but that success has not translated to the clinic for cancer therapy. A potential reason for this is that cells behave differently in monolayer than in the three-dimensional tumor, resulting in limited penetration and distribution of oligonucleotides in the tumor. This may be especially true when oligonucleotides are associated with nanocarriers such as lipoplexes and polyplexes, commonly used delivery vehicles for oligonucleotides. The multicellular tumor spheroid (MCTS), a three-dimensional model that closely resembles small avascular tumors and micrometastases, has been utilized as an intermediate between monolayer culture and in vivo studies for the screening of small-molecule drugs. However, spheroids have been little used for the study of various oligonucleotide delivery formulations. Here, we have evaluated the uptake and efficacy of splice-switching antisense oligonucleotides using various delivery modalities in two- and three-dimensional culture models. We find that the size of the delivery agent dramatically influences penetration into the spheroid and thus the biological effect of the oligonucleotides. We hypothesize that the MCTS model will prove to be a useful tool in the future development of oligonucleotide delivery formulations.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multicellular Tumor Spheroids as a Model for Assessing Delivery of Oligonucleotides in Three Dimensions

Carver

Xin

Juliano

2014

Molecular Therapy - Nucleic Acids

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“…Each test sample displayed a small size around 35 nm, which was speculated to have the potential for deep tumor penetration. 17,18 The zeta potential of the various EC-ME formulations was distributed between -15 mV and -16 mV, ie, a moderately negative charge, suggesting good stability and high cellular uptake. 19 As shown in Figure 1, the presence and concentration of VP16 did not change blank …”

Section: Results and Discussion Preparation And Characterization Of Ementioning

confidence: 99%

Microemulsion-based synergistic dual-drug codelivery system for enhanced apoptosis of tumor cells

Qu¹,

Ma²,

Sun³

et al. 2015

IJN

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A microemulsion-based synergistic dual-drug codelivery system was developed for enhanced cell apoptosis by transporting coix seed oil and etoposide into A549 (human lung carcinoma) cells simultaneously. Results obtained by dynamic light scattering showed that an etoposide (VP16)-loaded coix seed oil microemulsion (EC-ME) delivery system had a small size around 35 nm, a narrow polydispersity index, and a slightly negative surface charge. The encapsulating efficiency and total drug loading rate were 97.01% and 45.48%, respectively, by high-performance liquid chromatography. The release profiles at various pH values showed an obvious pH-responsive difference, with the accumulated amount of VP16 released at pH 4.5 (and pH 5.5) being 2.7-fold higher relative to that at pH 7.4. Morphologic alteration (particle swelling) associated with a mildly acidic pH environment was found on transmission electron microscopy. In the cell study, the EC-ME system showed a significantly greater antiproliferative effect toward A549 cells in comparison with free VP16 and the mixture of VP16 and coix seed oil. The half-maximal inhibitory concentration of the EC-ME system was 3.9-fold and 10.4-fold lower relative to that of free VP16 and a mixture of VP16 and coix seed oil, respectively. Moreover, fluorescein isothiocyanate and VP16 (the green fluorescent probe and entrapped drug, respectively) were efficiently internalized into the cells by means of coix seed oil microemulsion through intuitive observation and quantitative measurement. Importantly, an EC-ME system containing 20 μg/mL of VP16 showed a 3.3-fold and 3.5-fold improvement in induction of cell apoptosis compared with the VP-16-loaded microemulsion and free VP16, respectively. The EC-ME combination strategy holds promise as an efficient drug delivery system for induction of apoptosis and treatment of lung cancer.

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“…Nanoparticles are advantageous due to the fact that they are large enough to escape renal clearance and can passively target tumors through the enhanced permeation and retention effect [13]. However, nanoparticles tend to accumulate proximal to the blood vessels, leaving distal portions of the tumor untreated [14,15]. The lack of diffusion is a result of the composition and geometry of the ECM along with tightly packed cells of the tumor, limiting the pore size of the extracellular space [16].…”

Section: Introductionmentioning

confidence: 99%

Tumor Cell–Targeted Delivery of Nanoconjugated Oligonucleotides in Composite Spheroids

Carver

Xin²,

Juliano³

2014

Nucleic Acid Therapeutics

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Standard tissue culture has often been a poor model for predicting the efficacy of anti-cancer agents including oligonucleotides. In contrast to the simplicity of monolayer tissue cultures, a tumor mass includes tightly packed tumor cells, tortuous blood vessels, high levels of extracellular matrix, and stromal cells that support the tumor. These complexities pose a challenge for delivering therapeutic agents throughout the tumor, with many drugs limited to cells proximal to the vasculature. Multicellular tumor spheroids are superior to traditional monolayer cell culture for the assessment of cancer drug delivery, since they possess many of the characteristics of metastatic tumor foci. However, homogeneous spheroids comprised solely of tumor cells do not account for some of the key aspects of metastatic tumors, particularly the interaction with host cells such as fibroblasts. Further, homogeneous culture does not allow for the assessment of targeted delivery to tumor versus host cells. Here we have evaluated delivery of targeted and untargeted oligonucleotide nanoconjugates and of oligonucleotide polyplexes in both homogeneous and composite tumor spheroids. We find that inclusion of fibroblasts in the spheroids reduces delivery efficacy of the polyplexes. In contrast, targeted multivalent RGD-oligonucleotide nanoconjugates were able to effectively discriminate between melanoma cells and fibroblasts, thus providing tumor-selective uptake and pharmacological effects.

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Deep Penetration of Nanoparticulate Drug Delivery Systems into Tumors: Challenges and Solutions

Cited by 42 publications

References 11 publications

Multicellular Tumor Spheroids as a Model for Assessing Delivery of Oligonucleotides in Three Dimensions

Multicellular Tumor Spheroids as a Model for Assessing Delivery of Oligonucleotides in Three Dimensions

Microemulsion-based synergistic dual-drug codelivery system for enhanced apoptosis of tumor cells

Tumor Cell–Targeted Delivery of Nanoconjugated Oligonucleotides in Composite Spheroids

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