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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

Synthesis of SAHA-eAzide 1 and SAHA-aAzide 2. Reagents and conditions: a) 5-azidopentanoic acid, CMPI, DMAP, DMF, rt, 6 h, 14 % (1), 20 % (2).
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sch01: Synthesis of SAHA-eAzide 1 and SAHA-aAzide 2. Reagents and conditions: a) 5-azidopentanoic acid, CMPI, DMAP, DMF, rt, 6 h, 14 % (1), 20 % (2).

Mentions: In this report, we used suberoylanilide hydroxamic acid (SAHA) as a representative HDACi.10 SAHA has antitumor activity and structural elements that are shared by many Zn-dependent HDACi. To conjugate SAHA to the dendrimer scaffold, we modified SAHA with an azido-linker through the hydroxamic acid group. The modified SAHA was attached to the alkyne-modified G5 PAMAM dendrimer scaffold using the CuAAC reaction. Based on our prior work on cleavable linkers, we sought to evaluate the effects of two different linkages, an ester and an amide, on the functional properties of SAHA.7b The linker-modified SAHA compounds were synthesized as shown in Scheme 1. We modified SAHA with an azido-linker through either an ester bond (SAHA-eAzide 1) or an amide bond (SAHA-aAzide 2). The control dendrimer–HDACi conjugate (G5-eSAHA-Alkyne 5) and targeted dendrimer–HDACi conjugate (G5-FA-eSAHA-Alkyne 6) (Scheme 2) were synthesized using the CuAAC reaction of SAHA-eAzide 1 with the corresponding alkyne-modified dendrimers 3 and 4, respectively (Scheme 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)

Synthesis of SAHA-eAzide 1 and SAHA-aAzide 2. Reagents and conditions: a) 5-azidopentanoic acid, CMPI, DMAP, DMF, rt, 6 h, 14 % (1), 20 % (2).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

sch01: Synthesis of SAHA-eAzide 1 and SAHA-aAzide 2. Reagents and conditions: a) 5-azidopentanoic acid, CMPI, DMAP, DMF, rt, 6 h, 14 % (1), 20 % (2).
Mentions: In this report, we used suberoylanilide hydroxamic acid (SAHA) as a representative HDACi.10 SAHA has antitumor activity and structural elements that are shared by many Zn-dependent HDACi. To conjugate SAHA to the dendrimer scaffold, we modified SAHA with an azido-linker through the hydroxamic acid group. The modified SAHA was attached to the alkyne-modified G5 PAMAM dendrimer scaffold using the CuAAC reaction. Based on our prior work on cleavable linkers, we sought to evaluate the effects of two different linkages, an ester and an amide, on the functional properties of SAHA.7b The linker-modified SAHA compounds were synthesized as shown in Scheme 1. We modified SAHA with an azido-linker through either an ester bond (SAHA-eAzide 1) or an amide bond (SAHA-aAzide 2). The control dendrimer–HDACi conjugate (G5-eSAHA-Alkyne 5) and targeted dendrimer–HDACi conjugate (G5-FA-eSAHA-Alkyne 6) (Scheme 2) were synthesized using the CuAAC reaction of SAHA-eAzide 1 with the corresponding alkyne-modified dendrimers 3 and 4, respectively (Scheme 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