Trastuzumab-Conjugated Nanoliposomes for Targeted Capecitabine Delivery to Suppress HER2-Positive Breast Tumor: Efficacy Analysis in NOD SCID Mice Xenografts.
Treatment of advanced breast cancer has proven to be difficult. Routine chemotherapy has limitations due to unavoidable and dreaded adverse effects during and after treatment, necessitating the development of tailored therapies. Capecitabine is a commonly used anticancer drug that comes in tablet form for oral administration. However, high doses and frequent administration-related toxicities limit its efficacy in HER2-positive breast cancer patients.
The current work seeks to target capecitabine using experimental nanoliposomes coupled to trastuzumab (TZ) (HER2-targeting monoclonal antibody) and assess anticancer activity in a NOD SCID mice xenograft model of breast cancer. Experimental capecitabine-loaded trastuzumab-nanoliposomes (TZ-CNLs) were developed by a previously reported method. FESEM, AFM, TEM, zeta potential, and drug release studies were used to characterize TZ-CNLs. In vivo effectiveness of CNLs/TZ-CNLs was carried out in experimental mice and compared with the free capecitabine-treated group. Hematological, biochemical, and histopathological analyses of experimental CNLs/TZ-CNLs were conducted across different treatment groups compared with the control.
Experimental TZ-CNLs were spherical, smooth, and uniformly distributed, with an average size (198.6 nm), a zeta potential (-27.91 mV), and a drug loading (9.6±0.51%). The AFM indicated that TZ conjugation had no effect on texture. TZ-CNLs released 81.5 ± 3.05% capecitabine after 96 h, compared to CNLs/free capecitabine. After 12 days of treatment, TZ-CNLs significantly reduced tumor development (97.91 ± 3.0 mm3) compared to unconjugated CNLs/free capecitabine in NOD SCID mice xenografts. The enhanced antitumor activity observed with TZ-CNLs is consistent with HER2-targeted delivery mediated by TZ conjugation. Furthermore, TZ-CNL-treated animals maintained a healthier body-weight profile compared with free capecitabine and CNL-treated groups, suggesting improved treatment tolerability and reduced systemic toxicity. Plasma pharmacokinetic analysis indicated that administration of TZ-CNL-3 resulted in greater systemic availability of capecitabine, as well as prolonged mean residence time and increased volume of distribution, compared to free capecitabine and CNL-3. The study depicted an overall improvement in key biochemical parameters toward normal in animals treated with TZ-CNLs.
Overall, the promising preclinical outcomes, including tumor inhibition, improved hematologic and biochemical safety indices, and maintenance of organ histopathology, support the need for future preclinical investigations to determine whether TZ-CNLs may have application in HER2-positive breast cancer therapy.
The current work seeks to target capecitabine using experimental nanoliposomes coupled to trastuzumab (TZ) (HER2-targeting monoclonal antibody) and assess anticancer activity in a NOD SCID mice xenograft model of breast cancer. Experimental capecitabine-loaded trastuzumab-nanoliposomes (TZ-CNLs) were developed by a previously reported method. FESEM, AFM, TEM, zeta potential, and drug release studies were used to characterize TZ-CNLs. In vivo effectiveness of CNLs/TZ-CNLs was carried out in experimental mice and compared with the free capecitabine-treated group. Hematological, biochemical, and histopathological analyses of experimental CNLs/TZ-CNLs were conducted across different treatment groups compared with the control.
Experimental TZ-CNLs were spherical, smooth, and uniformly distributed, with an average size (198.6 nm), a zeta potential (-27.91 mV), and a drug loading (9.6±0.51%). The AFM indicated that TZ conjugation had no effect on texture. TZ-CNLs released 81.5 ± 3.05% capecitabine after 96 h, compared to CNLs/free capecitabine. After 12 days of treatment, TZ-CNLs significantly reduced tumor development (97.91 ± 3.0 mm3) compared to unconjugated CNLs/free capecitabine in NOD SCID mice xenografts. The enhanced antitumor activity observed with TZ-CNLs is consistent with HER2-targeted delivery mediated by TZ conjugation. Furthermore, TZ-CNL-treated animals maintained a healthier body-weight profile compared with free capecitabine and CNL-treated groups, suggesting improved treatment tolerability and reduced systemic toxicity. Plasma pharmacokinetic analysis indicated that administration of TZ-CNL-3 resulted in greater systemic availability of capecitabine, as well as prolonged mean residence time and increased volume of distribution, compared to free capecitabine and CNL-3. The study depicted an overall improvement in key biochemical parameters toward normal in animals treated with TZ-CNLs.
Overall, the promising preclinical outcomes, including tumor inhibition, improved hematologic and biochemical safety indices, and maintenance of organ histopathology, support the need for future preclinical investigations to determine whether TZ-CNLs may have application in HER2-positive breast cancer therapy.
Authors
Das Das, Satapathy Satapathy, Rahamathulla Rahamathulla, Alhamhoom Alhamhoom, Pattanaik Pattanaik, Chawla Chawla, Pattnaik Pattnaik, Rath Rath, Ahmed Ahmed, Pasha Pasha
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