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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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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DOI: https://doi.org/10.1007/s11095-015-1659-5