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Zolendronic Acid-Conjugated PLGA Ultrasmall Nanoparticle Loaded with Methotrexate as a Supercarrier for Bone-Targeted Drug Delivery

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Abstract

Drug delivery to deep-seated tissues such as bone has been a major complication till date. This preferential drug delivery is further important in targeting anti-tumour agents to bone metastasis owing to its complexity. The present study involves the formulation of PLGA nanoparticles and conjugation with zolendronic acid—a bisphosphonate which will anchor the nanosystem to bone due to its selective bone affinity. The conjugated nanosystem was characterized for particle size by TEM (average 36 nm) and morphology by AFM depicting surface irregularities due to ZOL conjugation on the surface of nanoparticles. NMR spectral data also showed the involvement of terminal -OH group of PLGA in bond formation with ZOL. Bone localization studies showed higher accumulation of the ZOL-conjugated nanosystem in bone than non-conjugated nanoparticles. This was confirmed with bone mineral affinity and specificity assay wherein the conjugated nanosystem was found to selectively bind to hydroxyapatite in comparison to other bone minerals. The biodistribution studies depicted that the conjugated nanosystem was selectively targeted to the bone area with concentrations of methotrexate reaching up to 127.4 ± 1.41 μg in 1 h. Hence, this multipronged approach using (1) ultrasmall size of nanoparticles, (2) bone selective polymer and (3) suitable bone-targeting agent resulted in mutual synergism for the specific delivery of the anti-tumour agent to the bone.

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Acknowledgements

The authors are thankful to ICMR (Indian Council of Medical Research, Govt of India, New Delhi) for providing financial assistance in the form of research fellowship (45/16/2014-Nan/BMS). The authors are obliged to Machen Product India Pvt. Ltd. (Mumbai), India, for providing the gift sample of MTX and ZOL and Evonik India for the gift sample of PLGA. Special thanks to Mount Carmel Institute, Bangalore for carrying out AFM analysis. The authors also acknowledge the assistance of Mr Venketesh (Bangalore Institute of Technology) and STIC, Cochin for carrying out the IR and NMR analysis, respectively.

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Authors and Affiliations

  1. Department of Pharmaceutics, Al-Ameen College of Pharmacy, Near Lalbagh Main Gate, Hosur Road, Bangalore, 560027, Karnataka, India

    Vinay Raichur & Kusum Devi Vemula

  2. Department of Pharmacology, Al-Ameen College of Pharmacy, Near Lalbagh Main Gate, Hosur Road, Bangalore, 27, Karnataka, India

    Naini Bhadri & Rema Razdan

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  1. Vinay Raichur
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  2. Kusum Devi Vemula
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Correspondence to Kusum Devi Vemula.

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Raichur, V., Vemula, K., Bhadri, N. et al. Zolendronic Acid-Conjugated PLGA Ultrasmall Nanoparticle Loaded with Methotrexate as a Supercarrier for Bone-Targeted Drug Delivery. AAPS PharmSciTech 18, 2227–2239 (2017). https://doi.org/10.1208/s12249-016-0691-z

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