A Multimodal Theranostic Nanoformulation That Dramatically Enhances Docetaxel Efficacy Against Castration Resistant Prostate Cancer

Julia C Bulmahn; Hilliard L Kutscher; Katherine Cwiklinski; Stanley A Schwartz; Paras N Prasad; Ravikumar Aalinkeel

doi:10.1016/j.xphs.2020.06.004

A Multimodal Theranostic Nanoformulation That Dramatically Enhances Docetaxel Efficacy Against Castration Resistant Prostate Cancer

J Pharm Sci. 2020 Sep;109(9):2874-2883. doi: 10.1016/j.xphs.2020.06.004. Epub 2020 Jun 11.

Authors

Julia C Bulmahn¹, Hilliard L Kutscher², Katherine Cwiklinski³, Stanley A Schwartz³, Paras N Prasad⁴, Ravikumar Aalinkeel³

Affiliations

¹ Institute for Lasers, Photonics and Biophotonics, Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260.
² Institute for Lasers, Photonics and Biophotonics, Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260; Division of Allergy, Immunology, and Rheumatology, Department of Medicine, State University of New York at Buffalo, Clinical Translational Research Center, Buffalo, New York 14203; Department of Anesthesiology, University at Buffalo, The State University of New York, Buffalo, New York 14203.
³ Division of Allergy, Immunology, and Rheumatology, Department of Medicine, State University of New York at Buffalo, Clinical Translational Research Center, Buffalo, New York 14203.
⁴ Institute for Lasers, Photonics and Biophotonics, Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260. Electronic address: pnprasad@buffalo.edu.

PMID: 32534879
DOI: 10.1016/j.xphs.2020.06.004

Abstract

In this work, a multifunctional hierarchical nanoformulation composed of biodegradable chitosan (CS) coated poly (lactic-co-glycolic acid) (PLGA) nanocarriers loaded with docetaxel (Doc) and interleukin-8 (IL-8) small interfering RNA (siRNA) electrostatically bound to upconversion nanoparticles (UCNPs), is developed to treat castration-resistant prostate cancer (CRPC). This theranostic nanoformulation facilitates simultaneous delivery of chemotherapy and gene therapy, as well as a bimodal optical and magnetic resonance imaging agent that could enable image-guided combination therapy. Poly-d-lysine coated NaYF₄; Yb20%, Er2%@NaYF₄; Gd50% core@shell UCNPs are effective siRNA transfection agents, and Er³⁺ doping provides upconversion imaging capabilities, while Gd³⁺ doping enables magnetic resonance contrast enhancement. These properties are maintained upon encapsulation in PLGA-CS. PLGA-CS nanocarriers containing Doc and UCNP-siRNA are 235 ± 5 nm with a zeta potential of +17 ± 4 meV, and have a high Doc encapsulation efficiency of 57 ± 6%. Compared to free Doc, this PLGA-CS nanoformulation containing Doc and UCNP-siRNA exhibits a dramatic decrease in IC₅₀ of ~14,000 fold (p < 0.001) through combination therapy in human PC-3 prostate cancer cells. This biocompatible, multimodal, theranostic nanoformulation demonstrates paradigm-shifting enhancement in anticancer activity over free Doc, with unique potential for use in image-guided combination therapy to treat CRPC.

Keywords: Cancer chemotherapy; Fluorescence spectroscopy; Gene therapy; Imaging methods; Nanoparticles; Nanotechnology; Poly (lactic-co-glycolic acid); Polymeric drug carrier; Small interfering RNA; Theranostic.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Survival
Docetaxel
Humans
Male
Nanoparticles*
Polylactic Acid-Polyglycolic Acid Copolymer
Precision Medicine
Prostatic Neoplasms, Castration-Resistant* / drug therapy

Substances

Docetaxel
Polylactic Acid-Polyglycolic Acid Copolymer