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Published on: September 3, 2013
PSMA-Targeted Dendrimer Delivery of Sorafenib Enhances MAPK Suppression and Anti-Angiogenic Activity in Prostate
Ritama Ghosh1, Anunay James Pulukuri2, Aqib Iqbal Dar2
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48104, United States.
Abstract:
Metastatic castration-resistant prostate cancer remains difficult to treat because conventional small-molecule therapies often lack tumor selectivity and have limited effective exposure. Sorafenib is a multikinase inhibitor that suppresses RAF-MEK-ERK signaling and angiogenesis, but its poor aqueous solubility limits its use. Here, we developed a prostate-specific membrane antigen (PSMA)-targeted poly(amidoamine) dendrimer-sorafenib conjugate, PD-Sora-CTT1298, using sequential CuAAC and SPAAC chemistry. The conjugate showed reproducible composition, high aqueous solubility, nanoscale size, and formulation stability. PD-Sora-CTT1298-Cy5 showed time-dependent PSMA-associated internalization in VCaP and PC3-PIP cells, with limited uptake in PSMA-negative DU145 cells. In VCaP cells, PD-Sora-CTT1298 produced greater in vitro suppression of viability, proliferation, MAPK signaling, VEGF-A secretion, endothelial tube formation, and autophagic vesicle accumulation than did free sorafenib. Combination with olaparib further reduced viability and increased apoptotic signaling. These findings support the further preclinical evaluation of PSMA-targeted dendrimer delivery for sorafenib-based prostate cancer therapy.
Insights
We developed a targeted drug delivery system for metastatic castration-resistant prostate cancer. This PSMA-targeted dendrimer conjugate improved sorafenib
Area of Science:
- Oncology
- Nanotechnology
- Drug Delivery
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) presents treatment challenges due to conventional therapies lacking tumor selectivity and having limited exposure.
- Sorafenib, a multikinase inhibitor, shows promise but is limited by poor aqueous solubility.
Purpose of the Study:
- To develop a novel prostate-specific membrane antigen (PSMA)-targeted poly(amidoamine) dendrimer-sorafenib conjugate for improved mCRPC therapy.
- To evaluate the conjugate's physicochemical properties, cellular uptake, and in vitro efficacy.
Main Methods:
- Utilized sequential CuAAC and SPAAC chemistry to synthesize the PSMA-targeted dendrimer-sorafenib conjugate (PD-Sora-CTT1298).
- Assessed conjugate composition, solubility, size, and stability.
- Investigated PSMA-associated cellular internalization in prostate cancer cell lines (VCaP, PC3-PIP, DU145).
- Evaluated in vitro suppression of viability, proliferation, MAPK signaling, VEGF-A secretion, and endothelial tube formation.
Main Results:
- The PD-Sora-CTT1298 conjugate exhibited reproducible composition, high aqueous solubility, nanoscale size, and formulation stability.
- PD-Sora-CTT1298-Cy5 demonstrated time-dependent, PSMA-specific internalization in VCaP and PC3-PIP cells.
- In VCaP cells, PD-Sora-CTT1298 significantly suppressed viability, proliferation, MAPK signaling, VEGF-A secretion, and endothelial tube formation more effectively than free sorafenib.
- Combination therapy with olaparib further enhanced viability reduction and apoptotic signaling.
Conclusions:
- PSMA-targeted dendrimer delivery of sorafenib offers enhanced therapeutic potential for prostate cancer.
- The developed conjugate demonstrates improved physicochemical properties and superior in vitro anti-cancer activity compared to free sorafenib.
- Further preclinical evaluation of this targeted delivery system is warranted for sorafenib-based prostate cancer treatment.
