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Design and Evaluation of Tumor-Specific Dendrimer Epigenetic Therapeutics.

Zong H, Shah D, Selwa K, Tsuchida RE, Rattan R, Mohan J, Stein AB, Otis JB, Goonewardena SN - ChemistryOpen (2015)

Bottom Line: Here we report the design and evaluation of tumor-specific dendrimer-HDACi conjugates.The HDACi was conjugated to the dendrimer using an ester linkage through its hydroxamic acid group, inactivating the HDACi until it is released from the dendrimer.Furthermore, we demonstrate that unlike traditional HDACi, dendrimer-HDACi conjugates do not affect tumor-associated macrophages, a recently recognized mechanism through which drug resistance emerges.

View Article: PubMed Central - PubMed

Affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Room 9220C MSRBIII 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA).

ABSTRACT
Histone deacetylase inhibitors (HDACi) are promising therapeutics for cancer. HDACi alter the epigenetic state of tumors and provide a unique approach to treat cancer. Although studies with HDACi have shown promise in some cancers, variable efficacy and off-target effects have limited their use. To overcome some of the challenges of traditional HDACi, we sought to use a tumor-specific dendrimer scaffold to deliver HDACi directly to cancer cells. Here we report the design and evaluation of tumor-specific dendrimer-HDACi conjugates. The HDACi was conjugated to the dendrimer using an ester linkage through its hydroxamic acid group, inactivating the HDACi until it is released from the dendrimer. Using a cancer cell model, we demonstrate the functionality of the tumor-specific dendrimer-HDACi conjugates. Furthermore, we demonstrate that unlike traditional HDACi, dendrimer-HDACi conjugates do not affect tumor-associated macrophages, a recently recognized mechanism through which drug resistance emerges. We anticipate that this new class of cell-specific epigenetic therapeutics will have tremendous potential in the treatment of cancer.

No MeSH data available.


Related in: MedlinePlus

Biological evaluation of the dendrimer SAHA conjugates in tumor-associated macrophages. RAW264.7 cells treated with 1 μm free SAHA showed significantly greater levels of apoptosis than RAW264.7 cells treated with the dendrimer–SAHA conjugates confirming the tumor-specificity of targeted dendrimer–SAHA conjugates. RAW264.7 cells were incubated with dendrimer SAHA conjugates and free SAHA for 3 d and assessed for apoptosis using the annexin/7AAD assay. Values represent the mean ± S.E.M. for n=3 independent experiments.
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fig03: Biological evaluation of the dendrimer SAHA conjugates in tumor-associated macrophages. RAW264.7 cells treated with 1 μm free SAHA showed significantly greater levels of apoptosis than RAW264.7 cells treated with the dendrimer–SAHA conjugates confirming the tumor-specificity of targeted dendrimer–SAHA conjugates. RAW264.7 cells were incubated with dendrimer SAHA conjugates and free SAHA for 3 d and assessed for apoptosis using the annexin/7AAD assay. Values represent the mean ± S.E.M. for n=3 independent experiments.

Mentions: One of the advantages of tumor-specific therapeutics is that many cancer drugs can also affect the immune system, reducing its ability to combat tumor initiation and progression. Macrophages contribute a large proportion of the cells in the tumor microenvironment and increased numbers are associated with a worse prognosis.15 Several studies have shown that HDACi are immunosuppressive through their effects on macrophages.16 Because of these macrophage effects, avoidance of HDAC inhibition in macrophages is desirable. To evaluate the capacity of the tumor-specific HDACi to avoid clearance and effects on macrophages, we examined the cytotoxic effects of free SAHA and the dendrimer–SAHA conjugates in the macrophage cell model RAW264.7. RAW264.7 cells were treated with free SAHA and the dendrimer–SAHA conjugates for 72 hours and evaluated for evidence of apoptosis using the An/7AAD assay mentioned above. At 72 hours, free SAHA induced apoptosis in RAW264.7 cells, while the dendrimer–SAHA conjugates had no effect, further confirming the cell specificity of the tumor-specific dendrimer–SAHA conjugates (Figure 3).


Design and Evaluation of Tumor-Specific Dendrimer Epigenetic Therapeutics.

Zong H, Shah D, Selwa K, Tsuchida RE, Rattan R, Mohan J, Stein AB, Otis JB, Goonewardena SN - ChemistryOpen (2015)

Biological evaluation of the dendrimer SAHA conjugates in tumor-associated macrophages. RAW264.7 cells treated with 1 μm free SAHA showed significantly greater levels of apoptosis than RAW264.7 cells treated with the dendrimer–SAHA conjugates confirming the tumor-specificity of targeted dendrimer–SAHA conjugates. RAW264.7 cells were incubated with dendrimer SAHA conjugates and free SAHA for 3 d and assessed for apoptosis using the annexin/7AAD assay. Values represent the mean ± S.E.M. for n=3 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4522184&req=5

fig03: Biological evaluation of the dendrimer SAHA conjugates in tumor-associated macrophages. RAW264.7 cells treated with 1 μm free SAHA showed significantly greater levels of apoptosis than RAW264.7 cells treated with the dendrimer–SAHA conjugates confirming the tumor-specificity of targeted dendrimer–SAHA conjugates. RAW264.7 cells were incubated with dendrimer SAHA conjugates and free SAHA for 3 d and assessed for apoptosis using the annexin/7AAD assay. Values represent the mean ± S.E.M. for n=3 independent experiments.
Mentions: One of the advantages of tumor-specific therapeutics is that many cancer drugs can also affect the immune system, reducing its ability to combat tumor initiation and progression. Macrophages contribute a large proportion of the cells in the tumor microenvironment and increased numbers are associated with a worse prognosis.15 Several studies have shown that HDACi are immunosuppressive through their effects on macrophages.16 Because of these macrophage effects, avoidance of HDAC inhibition in macrophages is desirable. To evaluate the capacity of the tumor-specific HDACi to avoid clearance and effects on macrophages, we examined the cytotoxic effects of free SAHA and the dendrimer–SAHA conjugates in the macrophage cell model RAW264.7. RAW264.7 cells were treated with free SAHA and the dendrimer–SAHA conjugates for 72 hours and evaluated for evidence of apoptosis using the An/7AAD assay mentioned above. At 72 hours, free SAHA induced apoptosis in RAW264.7 cells, while the dendrimer–SAHA conjugates had no effect, further confirming the cell specificity of the tumor-specific dendrimer–SAHA conjugates (Figure 3).

Bottom Line: Here we report the design and evaluation of tumor-specific dendrimer-HDACi conjugates.The HDACi was conjugated to the dendrimer using an ester linkage through its hydroxamic acid group, inactivating the HDACi until it is released from the dendrimer.Furthermore, we demonstrate that unlike traditional HDACi, dendrimer-HDACi conjugates do not affect tumor-associated macrophages, a recently recognized mechanism through which drug resistance emerges.

View Article: PubMed Central - PubMed

Affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Room 9220C MSRBIII 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA).

ABSTRACT
Histone deacetylase inhibitors (HDACi) are promising therapeutics for cancer. HDACi alter the epigenetic state of tumors and provide a unique approach to treat cancer. Although studies with HDACi have shown promise in some cancers, variable efficacy and off-target effects have limited their use. To overcome some of the challenges of traditional HDACi, we sought to use a tumor-specific dendrimer scaffold to deliver HDACi directly to cancer cells. Here we report the design and evaluation of tumor-specific dendrimer-HDACi conjugates. The HDACi was conjugated to the dendrimer using an ester linkage through its hydroxamic acid group, inactivating the HDACi until it is released from the dendrimer. Using a cancer cell model, we demonstrate the functionality of the tumor-specific dendrimer-HDACi conjugates. Furthermore, we demonstrate that unlike traditional HDACi, dendrimer-HDACi conjugates do not affect tumor-associated macrophages, a recently recognized mechanism through which drug resistance emerges. We anticipate that this new class of cell-specific epigenetic therapeutics will have tremendous potential in the treatment of cancer.

No MeSH data available.


Related in: MedlinePlus