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Synthesis and Evaluation of Substituted Poly(organophosphazenes) as a Novel Nanocarrier System for Combined Antimalarial Therapy of Primaquine and Dihydroartemisinin

Pharmaceutical Research volume 32, pages 2736–2752 (2015)Cite this article

Abstract

Purpose

The synthesis and evaluation of novel biodegradable poly(organophosphazenes) (3–6) namely poly[bis-(2-propoxy)]phosphazene (3) poly[bis(4-acetamidophenoxy)]phosphazene (4)poly[bis(4-formylphenoxy)]phosphazene (5) poly[bis(4-ethoxycarbonylanilino)]phosphazene (6) bearing various hydrophilic and hydrophobic side groups for their application as nonocarrier system for antimalarial drug delivery is described.

Methods

The characterization of polymers was carried out by IR, 1H-NMR and 31P-NMR. The molecular weights of these novel polyphosphazenes were determined using size exclusion chromatography with a Waters 515 HPLC Pump and a Waters 2414 refractive index detector. The degradation behavior was studied by 200 mg pellets of polymers in phosphate buffers pH 5.5, 6.8 and 7.4 at 37°C. The degradation process was monitored by changes of mass as function of time and surface morphology of polymer pellets. The developed combined drugs nanoparticles formulations were evaluated for antimalarial potential in P. berghei infected mice.

Results

These polymers exhibited hydrolytic degradability, which can afford applications to a variety of drug delivery systems. On the basis of these results, the synthesized polymers were employed as nanocarriers for targeted drug delivery of primaquine and dihydroartemisinin. The promising in vitro release of both the drugs from nanoparticles formulations provided an alternative therapeutic combination therapy regimen for the treatment of drug resistant malaria. The nanoparticles formulations tested in resistant strain of P. berghei infected mice showed 100% antimalarial activity.

Conclusions

The developed nanocarrier system provides an alternative combination regimen for the treatment of resistant malaria.

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Abbreviations

1H-NMR:

Proton nuclear magnetic resonance

31P-NMR:

Phosphorus nuclear magnetic resonance

ALP:

Alkaline phosphatase

ANOVA:

Analysis of variance

CPCSEA:

Committee for the purpose of control and supervision on experiments on animals

D2O:

Deuterated water

DHA:

Dihydroartemisinin

DMSO:

Dimethyl sulphoxide

DSC:

Differential scanning calorimetry

EDTA:

Ethylene diamine tetraacetic acid

EE:

Entrapment efficiency

ELISA:

Enzyme linked immuno sorbent assay

HPLC:

High performance liquid chromatography

IAEC:

Institutional animal ethical committee

IR:

Infrared

MHz:

Mega hertz

MST:

Mean survival time

Mw :

Molecular weight

NIMR:

National institute of malaria research, New Delhi, India

NP:

Nanoparticles

o/w:

Oil/water

PBS:

Phosphate buffer saline

PEG:

Polyethyleneglycol

ppm:

parts per million

PQ:

Primaquine

RBCs:

Red blood cells

SEM:

Scanning electron microscopy

SGOT:

Serum glutamic oxaloacetic transaminase

SGPT:

Serum glutamic pyruvate transaminase

TEM:

Transmission electron microscopy

Tg :

Glass transition temperature

TGA:

Thermogravimetric analysis

THF:

Tetrahydrofuran

UV:

Ultraviolet

Wt:

Weight

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors acknowledge the financial support received from Life Science Research Board (LSRB) of Defense Research and Development Organization (DRDO), New Delhi (India) DL/81/48222/LSRB-232/SH & DD/2011. We are also thankful to Sh. Parveen Garg, Chairman, I.S.F. College of Pharmacy, Moga (Punjab) (India) for providing the necessary facilities to carry out the research work. We also acknowledge Punjab Technical University, Jalandhar (Punjab) (India) for providing necessary facilities for research work.

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Authors and Affiliations

  1. Polymer Chemistry and Technology Research Laboratory, Department of Pharmaceutical Chemistry, Indo-Soviet Friendship (I.S.F) College of Pharmacy, Ferozepur Road, Moga, 142001, Punjab, India

    Sahil Kumar, R. S. R. Murthy & T. R. Bhardwaj

  2. Department of Pharmaceutical Chemistry, Shivalik College of Pharmacy, Nangal, Dist. Ropar, 140126, Punjab, India

    Rajesh K. Singh

  3. University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India

    T. R. Bhardwaj

  4. Research Scholar, Punjab Technical University, Jalandhar, Jalandhar-Kapurthala Highway, Kapurthala, 144601, India

    Sahil Kumar

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  1. Sahil Kumar
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  4. T. R. Bhardwaj
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Correspondence to T. R. Bhardwaj.

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Kumar, S., Singh, R.K., Murthy, R.S.R. et al. Synthesis and Evaluation of Substituted Poly(organophosphazenes) as a Novel Nanocarrier System for Combined Antimalarial Therapy of Primaquine and Dihydroartemisinin. Pharm Res 32, 2736–2752 (2015). https://doi.org/10.1007/s11095-015-1659-5

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KEY WORDS

  • biodegradable polyphosphazenes
  • degradation
  • dihydroartemisinin
  • drug-resistant malaria
  • nanoparticles
  • primaquine