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Tumor Microenvironment-Responsive Polymeric iRGD and Doxorubicin Conjugates Reduce Spontaneous Lung Metastasis in an
Zheng-Hong Peng1,2, Chinmay M Jogdeo1, Jing Li1
1Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 69198, USA.
Abstract:
Tremendous progress has been made in the field of nanomedicine for cancer treatment. However, most of the research to date has been focused on inhibiting primary tumor growth with comparatively less efforts directed towards managing tumor metastasis. Here, we introduce a polymeric conjugate P-DOX-iRGD that not only significantly suppressed primary tumor growth but also substantially inhibited pulmonary metastasis in an orthotopic mouse model of breast cancer. In addition, treatment with P-DOX-iRGD markedly reduced breast cancer-induced splenomegaly and liver hematopoiesis. Interestingly, contrasting results were seen for the free form and polymeric form of DOX in vitro and in vivo, which may be attributed to the enhanced permeability and retention (EPR) effect.
Insights
A novel polymeric conjugate, P-DOX-iRGD, effectively suppressed primary tumor growth and significantly inhibited pulmonary metastasis in breast cancer mouse models. This nanomedicine approach also reduced cancer-related organ enlargement and abnormal blood cell production in the liver.
Area of Science:
- Nanomedicine
- Oncology
- Polymer Chemistry
Background:
- Nanomedicine has advanced cancer treatment, primarily focusing on primary tumors.
- Managing cancer metastasis remains a significant challenge in oncology.
- Developing targeted therapies to combat metastatic disease is crucial.
Purpose of the Study:
- To develop and evaluate a novel polymeric conjugate, P-DOX-iRGD, for managing primary breast cancer and its metastasis.
- To investigate the in vitro and in vivo efficacy of P-DOX-iRGD compared to free Doxorubicin.
- To assess the impact of P-DOX-iRGD on cancer-induced organ pathologies.
Main Methods:
- Synthesis and characterization of the P-DOX-iRGD polymeric conjugate.
- Evaluation of P-DOX-iRGD efficacy in an orthotopic mouse model of breast cancer.
- Assessment of primary tumor growth inhibition and pulmonary metastasis reduction.
- Analysis of splenomegaly and liver hematopoiesis in treated mice.
- In vitro and in vivo comparison with free Doxorubicin.
Main Results:
- P-DOX-iRGD significantly suppressed primary tumor growth in the orthotopic mouse model.
- Substantial inhibition of pulmonary metastasis was observed with P-DOX-iRGD treatment.
- P-DOX-iRGD treatment markedly reduced breast cancer-induced splenomegaly.
- The conjugate also decreased abnormal liver hematopoiesis associated with breast cancer.
- Contrasting in vitro and in vivo results between free DOX and P-DOX-iRGD were noted, potentially due to the EPR effect.
Conclusions:
- The P-DOX-iRGD conjugate demonstrates significant potential as a nanomedicine for treating primary breast cancer and preventing metastasis.
- The enhanced efficacy of the polymeric form may be attributed to the enhanced permeability and retention (EPR) effect.
- This study highlights the importance of targeting metastasis alongside primary tumor growth in cancer therapy.
