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Anticancer and Immunostimulatory Activity by Conjugate of Paclitaxel and Non-toxic Derivative of LPS for Combined Chemo-immunotherapy

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ABSTRACT

Purpose

Cancer is a multifactorial syndrome; hence, multidimensional therapy with a chemo-immunotherapeutic conjugate could be more effective in curing the disease.

Methods

We used SP-LPS, a bio-polymer having potent immunostimulatory activity, for conjugation with paclitaxel to make a chemo-immunotherapeutic conjugate. Its physicochemical characterization was done by HPLC, NMR and IR spectra. Stability was measured at different pH, temperature and in tissue homogenates. Chemotherapeutic and immunostimulatory activity was evaluated in vitro and also in tumor microenvironment.

Results

The conjugate self assembled into nanoparticulate structure, probably due to micelle formation. Stability was pH and temperature dependent. The conjugate exhibited chemotherapeutic and immunotherapeutic activity in vitro. In vivo antitumor activity was significantly higher and a higher percentage of activated immune cells were found in the tumor microenvironment of the conjugate-treated mice as compared to Taxol®-treated group.

Conclusions

This conjugate is a potential chemo-immunotherapeutic compound for the treatment of cancer with advantages over present day chemotherapy with Taxol in terms of higher anticancer activity, less toxicity and ease of delivery.

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ACKNOWLEDGMENTS & DISCLOSURES

This work was supported by the NII core grant. We sincerely thank Dr. Monica Sund for helping in the NMR studies. We are also thankful to the Advanced Instrumentation Research Facility of Jawaharlal Nehru University, New Delhi for the IR studies.

Author information

Author notes

  1. Swapna Mamilapally

    Present address: Celavie Biosciences, LLC, Oxnard, California, 93030, USA

Authors and Affiliations

  1. Product Development Cell-I, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India

    Aniruddha Roy, Sourav Chandra, Swapna Mamilapally, Pramod Upadhyay & Sangeeta Bhaskar

Authors
  1. Aniruddha Roy
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  2. Sourav Chandra
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  3. Swapna Mamilapally
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Corresponding authors

Correspondence to Pramod Upadhyay or Sangeeta Bhaskar.

Electronic Supplementary Material

HPLC elution profile of PLC, PTX and PTX succinate (Supplementary Fig. 1) and body weight and tissue histology of treated animals for toxicity study (Supplementary Fig. 2) are included in the Supporting Information.

Supplementary Figure 1

HPLC elution profile of PTX, PTX succinate and PLC. All of the compounds were dissolved in DMSO and run in Shimadzu UFLP HPLC system. The mobile phase consisted of 60:40 (v/v), acetonitrile : water and delivered at a flow rate of 1.0 mL/minute. The reverse phase column used was Phenomenex RPC18 column (300 × 5 mm, pore size 5 μm). Detection was done at 228 nm. No overlapping peak of either PTX or PTX succinate in the PLC indicated purity of the conjugate. Short elution time of PLC also suggested polar nature compared to both PTX and PTX succinate. (JPEG 9181 kb)

Supplementary Figure 2

Toxicity study of the conjugate. Mice were intravenously administered with 400 μg/animal dose of PTX delivered either as the commercial formulation, Taxol or PLC. One set of mice were monitored for 14 days and regular checkup of body weight was done. Some animals were sacrificed after 48 h of injection and histopathological study was done on different organs. A. Comparison of body weight of PLC treated and Taxol treated mice with saline treated mice (control). B. Histopathological examination of different organs of PLC treated and Taxol treated mice compared to saline treated mice. No toxic manifestation was found in the PLC treated animals with respect to both body weight and tissue histology. (JPEG 5497 kb)

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Roy, A., Chandra, S., Mamilapally, S. et al. Anticancer and Immunostimulatory Activity by Conjugate of Paclitaxel and Non-toxic Derivative of LPS for Combined Chemo-immunotherapy. Pharm Res 29, 2294–2309 (2012). https://doi.org/10.1007/s11095-012-0756-y

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  • DOI: https://doi.org/10.1007/s11095-012-0756-y

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