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Dear All,
I will be interested in understanding how nanoparticles given by oral
route remains in systemic circulation for more than 1 day or even upto
7 days.
Regards,
Tushar Nahata
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Dear all
Studies have been reported that nanoparticles would have a longer
circulation. It might be because of smaller size so that escape form
the RES uptake, slower polymer release rate, Pgp Modulation effect.
I am also interested to hear some more comments on this issue.
Kindly correct me if i am wrong.
Thank you
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Hi Karthik,
You are right about the size. Way back in 1987, we had shown this very
different pharmacokinetics of very small unilamellar liposomes, about
23 nm in size.
see:
Uptake of small liposomes by non-reticuloendothelial tissues.
Karl J. Hwang, Milind M. Padki, Donald D. Chow, Herbert E. Essien, J.
Y. Lai and Paul L. Beaumier. Biochim Biophys Acta 901 (1987) 88-96.
Hope this helps,
Milind
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Hi Tushar,
These are two separate issues:
1. How do they get into ciculation, when administered by the oral
route: The answer to that is " Nanoparticles administered orally can
be absorbed, albeit in small quantities, not only by way of the
membranous epithelial cells (M-cells) of the Peyer's patches in the
gut-associated lymphoid tissue (GALT) but also by the much more
numerous gut enterocytes. (A.T. Florence, 2005).
2. How do they escape phagocytosis: Actually they are cleared from the
bloodstream within minutes upon intravenous injection, depending on
their size and surface characteristics. We need to coat them in some
way to avoid "opsonization" followed by phagocyctosis.
Surface modifications using polyethylene glycol (PEG) have been
achieved in the case of polymeric drug carriers and liposomes
[1,2]. Another work also showed that the use of the amphiphilic
diblock copolymer monomethoxypoly( ethylene oxide)-poly(lactic acid)
(MPEO-PLA) for the preparation of nanoparticles delays their
phagocytosis [3]. However, the efficacy of the coating procedure to
hinder opsonization depends on the chain length and the density of
these moieties at the surface of the particles [4].
[1] Illum L, Davis SS, Muller RH, Mak E, West P. The organ
distribution and circulation time of intravenously injected
colloidal carriers sterically stabilized with a block copolymer--
poloxamine 908. Life Sci 1987;40:367-74.
[2] Allen TM. Long-circulating (sterically stabilized) liposomes for
targeted drug delivery. Trends Pharmacol Sci 1994;15:215-20.
[3] Bazile D, Michalon JP, Prud'homme C, Spenlehauer G, Veillard
M. Nanoparticles having a prolonged reticulo-endothelial
system capture rate. French Patent No. 08041, 1991.
[4] Bazile D, Prud'homme C, Bassoullet MT, Marlard M, Spenlehauer
G, Veillard M. Stealth Me.PEG-PLA nanoparticles avoid
uptake by the mononuclear phagocytes system. J Pharm Sci
1995;84:493-8.
Hope this helps,
Milind
[quoted from: Therapeutic potential of nanoparticulate systems for
macrophage targeting
Fatiha Chellat
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The following message was posted to: PharmPK
Dear Tushar/Karthik,
In general nanoparticles will not remain in systemic circulation for
long time. The nanoparticles given by oral route are absorbed rapidly
and also cleared off rapidly from the blood stream. The high clearance
of nanoparticles from blood stream is because of the selective uptake
by reticuloendothelial systems (RES) due to their small size.
Many of research works have proved the above fact, wherein the authors
reported lower AUC in plasma concentration-time curve in comparison to
tissue concentration-time curve. The nanoparticles accumulation and
retention in tissues was pretty higher in comparison to pure drug
formulations due to increased uptake in nanoparticle form [1].
So, many attempts were made to circumvent the problem of uptake by
phagocytosis. The most used approach for this purpose is coating with
hydrophilic polymers like PEG and poloxamers as the uptake by RES is
dependent on the hydrophobicity of the particles.
Nanoparticles to some extent have p-gp modulation effect.
Nanoparticles could limit the binding to p-gp by masking the
characteristics of original drug [2]. However, contrasting result were
obtained by few authors [3].
[1]Teng Kuang Yeh et al. Formulating Paclitaxel in Nanoparticles
Alters Its Disposition. Pharmaceutical Research. 22(6), 2005,867-874.
[2]Joanna M. Koziara et al. Paclitaxel nanoparticles for the potential
treatment of brain tumors. Journal of Controlled Release. 99(2), 2004,
259-269.
[3] Mahesh D. Chavanpatil et al. Susceptibility of nanoparticle-
encapsulated paclitaxel to P-glycoprotein-mediated drug efflux.
International Journal of Pharmaceutics. 320(1-2), 2006, 150-156.
Thanks & Regards
Sivacharan Kollipara
Research Associate
Metabolism & Pharmacokinetics
Ranbaxy Laboratories Ltd
Gurgaon-122015, India
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Sivacharan:
I want to discuss some of the points you mentioned.
1.In general nanoparticles will not remain in systemic circulation
for long time. The nanoparticles given by oral route are absorbed
rapidly and also cleared off rapidly from the blood stream. The high
clearance of nanoparticles from blood stream is because of the
selective uptake by reticuloendothelial systems (RES) due to their
small size.
> I agree with you that nanoparticles (NPs) do not remain for a long
time once they get into systemic circulation because of the
opsonization process stimulatates RES to catch those particles but it
doesn't relate to any size.
2.Many of research works have proved the above fact, wherein the
authors reported lower AUC in plasma concentration-time curve in
comparison to tissue concentration-time curve. The nanoparticles
accumulation and retention in tissues was pretty higher in comparison
to pure drug formulations due to increased uptake in nanoparticle
form [1].
> Here we need to be little cautious to come to this conclusion.
There are various factors that play role in ADME. It depends upon the
nature of drug molecule (lipophilic/lipophobic), drug delivery system
(type and nature of polymer) used for controlled/targeted delivery.
3.So, many attempts were made to circumvent the problem of uptake by
phagocytosis. The most used approach for this purpose is coating with
hydrophilic polymers like PEG and poloxamers as the uptake by RES is
dependent on the hydrophobicity of the particles.
>Please provide some data if you have for "uptake by RES is
dependent on the hydrophobicity of the particles".
4.Nanoparticles to some extent have p-gp modulation effect.
Nanoparticles could limit the binding to p-gp by masking the
characteristics of original drug [2]. However, contrasting result
were obtained by few authors [3].
> I agree with you that NPs upto some extent help drug (if P-gp
substrate) from P-gp efflux mechanism. But after getting released from
NP into the cell the drug get kicked out of cell by P-gp pump. In
general NPs have better cell uptake through endocytosis or receptor
mediated uptake (if NP has any ligand)than drug in solution form.
I was a coauthor in the reference you mentioned here "Susceptibility
of nanoparticle- encapsulated paclitaxel to P-glycoprotein-mediated
drug efflux. International Journal of Pharmaceutics. 320(1-2), 2006,
150-156" . Here we had encapsulated taxol in PLGA nanoparticles where
PLGA polymer does not have any P-gp modulating activity so once the
taxol get released into cytoplasm get effluxed out by P-gp. It is
important to know the characteristic of polymer encapsulating the
drug. If you have pluronic NP (has P-gp modulating activity)
encapsulating P-gp substarte will show better cytosolic drug
accumulation compare to PLGA NP formulations. Recently I published
couple of articles in Biomaterials and JCR on the same topic.
Please feel free to discuss if you have any questions.
Thanks
Yogesh Patil, PhD
Research Scientist
Impax Laboratories Inc.
Hayward, CA USA
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The following message was posted to: PharmPK
Dear Yogesh Patil,
Thanks for your response to my post and making some valuable points. I
would like to discuss some of issues you have mentioned.
1. Please provide some data if you have for "uptake by RES is
dependent on the hydrophobicity of the particles"
Detailed description about this topic can be found in:
> Gert Storm et al. Surface modification of nanoparticles to oppose
uptake by the mononuclear
> phagocyte system. Advanced Drug Delivery Reviews 17 (1995) 31-48.
> S.D. Troester et al. International Journal of Pharmaceutics.
61(1-2),1990, 85-100.
in this study authors coated poly(methyl methacrylate) nanoparticles
with various surfactants such as poloxamers, poloxamines, Brij 35 etc.
by coating with these, they have found that poloxamer, poloxamine were
able to reduce the liver (RES organ) uptake by 30%. Moreover, the
uptake to other non-RES organs increased significantly by coating with
surfactants.
> S. M. Moghimi et al. Biochemical and Biophysical Research
Communications. 177(2), 1991, .861-866
It was clearly mentioned in abstract "A recent development in
prolonging the circulation time of drug carriers, such as liposomes
and microspheres, has been to minimize their removal by macrophages of
the reticulo endothelial system by covering their surface with
hydrophilic polymers such as poloxamers, poloxamines and poly
(ethylene glycols)"
2. Nanoparticles have ability to circumvent P-gp effect to some
extent. You are right in saying that after getting released, the drug
gets kicked out of the cell by P-gp. But it depends on the release
characteristics of the drug from nanoparticles, like how much drug has
got released at that point of time from NP. It depends on the polymer
& drug characteristics and method of preparation as they determine the
release kinetics and absorption behavior of NP. It might be in some
cases the release of drug from NP is so fast that it will be
accessible to P-gp in cell. There might be other cases where the
release rate is slow and by the time drug is released, nanoparticles
are absorbed and far away from p-gp and hence limiting the
accessibility of drug to P-gp. So to SOME EXTENT it doesn't matter
whether NP were encapsulated with PLGA or Pluronic block polymers.
Looking from another angle, Pluronic F68 (used widely in nanoparticles
formulations as a stabilizer compared to other Pluronics) has very
little or no effect on P-gp.
Ref: Alexander V. Kabanov et al. Pluronic(R) block copolymers for
overcoming drug resistance in cancer. Advanced Drug Delivery Reviews
54 (2002) 759-779.
Thanks & Regards
Sivacharan Kollipara
Research Associate
Metabolism & Pharmacokinetics
Ranbaxy Laboratories Ltd
Gurgaon-122015, India
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