Back to Search
Start Over
Tumor hypoxia directed multimodal nanotherapy for overcoming drug resistance in renal cell carcinoma and reprogramming macrophages
- Source :
- Biomaterials. 183:280-294
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Drug resistance is one of the significant clinical burden in renal cell carcinoma (RCC). The development of drug resistance is attributed to many factors, including impairment of apoptosis, elevation of carbonic anhydrase IX (CA IX, a marker of tumor hypoxia), and infiltration of tumorigenic immune cells. To alleviate the drug resistance, we have used Sorafenib (Sor) in combination with tumor hypoxia directed nanoparticle (NP) loaded with a new class of apoptosis inducer, CFM 4.16 (C4.16), namely CA IX-C4.16. The NP is designed to selectively deliver the payload to the hypoxic tumor (core), provoke superior cell death in parental (WT) and Everolimus-resistant (Evr-res) RCC and selectively downmodulate tumorigenic M2-macrophage. Copper-free ‘ click ’ chemistry was utilized for conjugating SMA-TPGS with Acetazolamide (ATZ, a CA IX-specific targeting ligand). The NP was further tagged with a clinically approved NIR dye (S0456) for evaluating hypoxic tumor core penetration and organ distribution. Imaging of tumor spheroid treated with NIR dye-labeled CA IX-SMA-TPGS revealed remarkable tumor core penetration that was modulated by CA IX-mediated targeting in hypoxic-A498 RCC cells. The significant cell killing effect with synergistic combination index (CI) of CA IX-C4.16 and Sor treatment suggests efficient reversal of Evr-resistance in A498 cells. The CA IX directed nanoplatform in combination with Sor has shown multiple benefits in overcoming drug resistance through (i) inhibition of p -AKT, (ii) upregulation of tumoricidal M1 macrophages resulting in induction of caspase 3/7 mediated apoptosis of Evr-res A498 cells in macrophage-RCC co-culturing condition, (iii) significant in vitro and in vivo Evr-res A498 tumor growth inhibition as compared to individual therapy, and (iv) untraceable liver and kidney toxicity in mice. Near-infrared (NIR) imaging of CA IX-SMA-TPGS-S0456 in Evr-res A498 RCC model exhibited significant accumulation of CA IX-oligomer in tumor core with >3-fold higher tumor uptake as compared to control. In conclusion, this proof-of-concept study demonstrates versatile tumor hypoxia directed nanoplatform that can work in synergy with existing drugs for reversing drug-resistance in RCC accompanied with re-education of tumor-associated macrophages, that could be applied universally for several hypoxic tumors.
- Subjects :
- 0301 basic medicine
Sorafenib
Programmed cell death
Cell Survival
Biophysics
Mice, Nude
Antineoplastic Agents
Apoptosis
Bioengineering
Caspase 3
Proof of Concept Study
Article
Permeability
Theranostic Nanomedicine
Biomaterials
Mice
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
In vivo
Cell Line, Tumor
medicine
Animals
Humans
Everolimus
Carbonic Anhydrase IX
Carcinoma, Renal Cell
Drug Carriers
Tumor hypoxia
Chemistry
Macrophages
Cellular Reprogramming
Combined Modality Therapy
Cell Hypoxia
Kidney Neoplasms
Acetazolamide
030104 developmental biology
Cell killing
Drug Resistance, Neoplasm
Mechanics of Materials
030220 oncology & carcinogenesis
Ceramics and Composites
Cancer research
Nanoparticles
Tumor Hypoxia
Female
medicine.drug
Subjects
Details
- ISSN :
- 01429612
- Volume :
- 183
- Database :
- OpenAIRE
- Journal :
- Biomaterials
- Accession number :
- edsair.doi.dedup.....cf65eb51d73a3c422c7bdb6241257ce7