Synergistic action of lactoferrin in enhancing the safety and effectiveness of docetaxel treatment against prostate cancer

• Published in: Cancer chemotherapy and pharmacology 2023-05, Vol.91 (5), p.375-387
• Main Authors: Muj, Chukhu, Mukhopadhyay, Satyajit, Jana, Pritikana, Kondapi, Anand K.
• Format: Article
• Language: English
• Subjects: Alkaline phosphatase; Animals; Anticancer properties; Antineoplastic Agents - adverse effects; Antineoplastic Agents - chemistry; Antitumor activity; Bioavailability; Biological activity; Biomarkers; C-reactive protein; Cancer Research; Cell division; Cell Line, Tumor; Chemical modification; Chemotherapy; Conjugation; Creatinine; Docetaxel; Drug Carriers - chemistry; Effectiveness; Enzyme-linked immunosorbent assay; Histochemical analysis; Humans; Immunology; Inhibitor drugs; Interferon; Kidneys; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactoferrin; Lactoferrin - chemistry; Lactoferrin - metabolism; Lactoferrin - pharmacology; Leukocytes; Leukocytes (neutrophilic); Localization; Male; Medicine; Medicine & Public Health; Metastases; Metastasis; Mitosis; Nanoparticles; Nanoparticles - chemistry; Oncology; Original Article; Pharmacology/Toxicology; Prostate cancer; Prostatic Neoplasms - drug therapy; Rats; Toxicity; Transmission electron microscopy; Tumor cells; Tumors; Uric acid; γ-Interferon
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-023-04524-9

Background Tumor metastasis is promoted by an immunosuppressive environment. Lactoferrin (Lf) is known to regulate immunological activity in tumor cells and inhibit processes associated with tumor metastasis. A delivery of lactoferrin with docetaxel (DTX) in prostate cancer cells in the form of DTX-loaded lactoferrin nanoparticles (DTX-LfNPs) would provide a dual activity wherein the lactoferrin affects metastasis and DTX chemotherapeutically inhibits mitosis and cell division. Methods DTX-LfNPs were prepared using sol–oil chemistry, and particles were characterized using transmission electron microscopy. Antiproliferation activity was analyzed in prostate cancer Mat Ly Lu cells. The target localization and efficacy of DTX-LfNPs were studied in an orthotopic prostate cancer induced by Mat Ly Lu cells in a rat model. Biomarkers were estimated using ELISA and biochemical reactions. Results DTX was loaded in pure Lf nanoparticles without involving any chemical modification and conjugation, thus when these nanoparticles are delivered in cancer cells both DTX and Lf will be present in biologically active forms. DTX-LfNps exhibit a spherical morphology of dimension of 60 ± 10 nm with DTX Encapsulation Efficiency of 62.06 ± 4.07%. Competition experiments using soluble Lf confirm that DTX-LfNPs enter prostate cancer cells through the Lf receptor. DTX-LfNPs exhibit an improved anti-proliferative activity by 2.5 times compared to DTX. Further, analysis of the bioavailability of the drug in the prostate showed that DTX-LfNPs increased drug bioavailability in the prostate by two times more than the DTX. The analysis of efficacy in the Mat Ly Lu cells-induced orthotopic prostate cancer model showed that DTX-LfNPs significantly enhanced the anti-cancer activity compared to DTX in terms of regression of weight and volume of prostate tissue, the efficacy was confirmed by histochemical analysis. Lf provides synergistic activity along with DTX in inhibiting metastasis as assessed by the reduction of lactate dehydrogenase, alkaline phosphatase, TNF alpha, and IFNγ. LfNPs facilitate higher DTX localization along with Lf-mediated protection from DTX-associated toxicity to neutrophils and kidneys as assessed by C-reactive protein, creatinine, and uric acid. Thus, DTX LfNPs show a dual action by enhancing DTX bioavailability in prostate along with Lf-mediated suppression of metastasis as well as DTX-associated toxicity. Conclusion In conclusion, DTX-LfNPs enhance the bioavailabi