it includes all aspects regarding Nanoparticles and Nanoparticulate drug delivery system

1. Dadasaheb Balpande College of Pharmacy , Besa, Nagpur -440037

2.  INTRODUCTION
 HISTORY
 BASICS
 TYPES OF NANOPARTICLES
 LITERARURE REVIEW
 NANOPARTICULATE DRUD DELIVERY SYSTEM (NPDDS)
 TYPES OF NPDDS
 APPLICATIONS
 ADVANTAGES
 FACTORS
 METHODS OF PREPARATION
 MECHANISM OF DRUG RELEASE
 EVALUATION PARAMETER
 REFERENCES
2

3. NANOPARTICLES
 Nanoparticles are solid colloidal particles consisting of macromolecular
substances that vary in size from 10 nm to 1,000 nm.
 The drug of interest is dissolved, entrapped, adsorbed attached or encapsulated
into the Nanoparticle matrix.
 Depending upon the method of preparation, nanoparticles, nanospheres or
nano capsules can be obtained with different properties and release
characteristics for the encapsulated therapeutic agent .
Figure 1 : Nanoparticulate system
3

4.  Nanoparticles as a drug delivery vehicle were first developed by
Spieser and co-workers in the late 1960s.
 Early 1970s the cross linked polyacrylamide nanoparticles were
produced.
 Scheffel et al developed a process for production of radiolabelled
albumin particles for imaging purpose in nuclear medicines.
 Widder et al incorporated magnetic particles into the nanoparticles for
targeting of these particles by means of magnetic field.
4

5.  Nanotechnology: comprises technological developments on the nanometer scale,
usually 0.1 to 100 nm. Nano is Greek word for dwarf, and nanoscience deals
with the study of molecular and atomic particles.
The application of nanotechnology in pharmaceutical field includes formulation
of Nanoparticles, Nanosuspension, Nanospheres, Nanocapsules, and
Nanoemulsion.
 Nanosuspensions : They are colloidal dispersions of nanosized drug particle
that are produced by suitable method and stabilized by suitable stabilizer .
 Nanoparticles: They are solid colloidal particles sized from 30-100 nm .
 Nanospheres : Polymer matrices in which drug is dissolved or dispersed .
 Nanocapsules : Consists of polymer wall entrapping an oily core in which
the drug is dissolved.
5

6. Sr.
No.
Types Material Used Applications
1 Polymeric Nanoparticles Biodegradable polymer Controlled and Targeted
Drug Delivery
2 Solid Lipid Nanoparticles Melted Lipid Dispersed in
aqueous surfactant
Least toxic and more
stable colloidal carrier
systems as alternative to
polymers
3 Nanocrystals Nanosuspensions Drug powder is dispersed in a
surfactant solution
Stable systems for
controlled delivery of
poorly water soluble drugs
4 Polymeric Micelles Amphiphilic block copolymers Systemic and Controlled
delivery of water insoluble
drugs
5 Liposomes Phospholipid Vesicles Controlled and targeted
drug delivery
6

7. Sr.
No.
Types Material used Applications
6 Dendrimers Tree like molecules with defined
cavities
Drug Targeting
7 Magnetic Nanoparticles An inorganic core of iron oxide
coated with polymer such as
dextran
Drug targeting , Diagnosting
tool in biology and medicine
8 Gold Nanoshells Dielectric core and metal shell (
gold sulphide or silica and gold
resp.)
Tumour targeting
9 Nanowires and Carbon
Nanotubes
Metals , semiconductors or
carbon
Gene and DNA delivery
10 Ferrofluids Iron oxide magnetic
nanoparticles surrounded by a
polymeric layer
For capturing cells and other
biological targets from blood
or other fluids and tissue
samples
7

8. Figure 2 : Types of Nanoparticles 8

9. Authors Name and Year Aim / Title / Work Observation and
Conclusions
1. - Yogita patil sen
- 2018
Nanoparticles : Smart drug delivery
system
nanoparticles have proven to provide an
excellent drug carrier system for smart
and targeted delivery. By clever
engineering it has been possible to
manufacture and fabricate various types
of nanoparticles, each with its own
advantages and suitability for
nanotechnology applications.
3. -Jayanta Kumar Patra , Gitishree
Das, Leonardo Fernandes
Fraceto
- 2018
Nano based drug delivery systems:
recent developments and future
prospects
The present review discusses the recent
advances in nanomedicines, including
technological progresses in the delivery
of old and new drugs as well as novel
diagnostic methodologies.
3. -Jiemin Wang, Xiongbin Hu &
Daxiong Xiang
- 2018
Nanoparticle drug delivery systems:
an excellent carrier for tumor peptide
vaccines
The application of nano drug delivery
system to tumor vaccine has become the
focus of anti-tumor vaccine research. It
plays an important role in improving the
immune effect of anti-tumor vaccine and
overcoming the immunosuppression
LITERATURE REVIEW
9

10. 4. - Abdullah Maleki,
Ali Reza Karimpour, Solmaz Maleki
- 2017
The role of mechanical
engineering in the development
of nano drug delivery systems; a
review
The present study aimed to
collect useful evidence from the
scientific literature regarding
the role of mechanical
engineering in designing nano-
based pharmaceutical delivery
systems.
5. C.Karuppusamy, and P.Venkatesan
- 2017
Role of Nanoparticles in Drug
Delivery System : A
Comprehensive review
Nanocarriers as drug delivery
systems are designed to improve
the pharmacological and
therapeutic properties of
conventional drugs.
6. Mukarram Anees,Muhammad Irfan
Masoo, Mahwish ilyas, Talib Hussain
- 2016
NANOPARTICLES AS A
NOVEL DRUG DELIVERY
SYSTEM: A Review
The nanoparticles have wide
range of applications as drug
carriers, and targeting specific site
in the body.
7. Sriharitha, Preethi J, Hemanth Swaroop
- 2014
A Review on Nanoparticles in
Targeted Drug Delivery System
Novel drug delivery systems plays
a major role in site specific drug
delivery (Targeted drug delivery)
compared to conventional dosage
forms due to its advantages in site
specificity and stability.
10

11. 8. Suresh Sagadevan, Mathan
Periasamy
- 2013
A REVIEW ON ROLE OF
NANOSTRUCTURES IN DRUG
DELIVERY SYSTEM
Nanomedicine is the application of
nanostructures in an innovative way
to develop new approaches and
therapies. Products of
nanotechnology are expected to
revolutionize modern medicine, as
evidenced by recent scientific
advances and global initiatives
9. Ashara Kalpesh C.,Paun Jalpa
S.,Soniwala M.M.,Chavada
J.R.,Badjatiya J.K
- 2013
NANOPARTICULATE DRUG
DELIVERY SYSTEM: A NOVEL
APPROACH
Nanoparticles are used very much
because of more bioavailability of drug
as compare to conventional
formulations almost 3 to 4 folds
increment of bioavailability as compare
to original so Nanoparticles are used
very much in pharmaceutical sciences
& various faculties of sciences as well .
10. Prabhjot kaur, Loveleenpreet kaur
and MU. Khan
- 2012
NANOPARTICLES AS A NOVEL
DRUG DELIVERY SYSTEM: A
REVIEW
Nanoparticulate systems have great
potentials, being able to convert poorly
soluble, poorly absorbed and labile
biological active substance into
promising deliverable drugs.
11. Natarajan Jawahar, Meyyanathan
SN
- 2012
Polymeric nanoparticles for drug
delivery and targeting: A
comprehensive review
Nanotechnology is an exciting novel
field with hopes for improvements in
wide variety of uses in drug delivery in
pharmaceutical research.
11

12.  Nanoparticulate drug-delivery systems (NPDDSs) are explored for the purpose
of solving the challenges of drug delivery.
 Coming in many shapes and sizes, most carriers are less than 100 nm in
diameter.
 NPDDSs provide methods for targeting and releasing therapeutic compounds
in much defined regions.
 These vehicles have the potential to eliminate or at least ameliorate many
problems associated with drug distribution.
 As many drugs have a hydrophobic component, they often suffer from
problems of precipitation in high concentration, and there are many examples
of toxicity issues with excipients designed to prevent drug aggregation.
 To combat these issues, many NPDDSs provide both hydrophobic and
hydrophilic environments, which facilitate drug solubility. 12

13.  Nanoparticulate drug delivery system for oral administration.
 Nanoparticulate aerosol drug delivery system .
 Nanoparticulate drug delivery system for topical administration.
 Parentral Nanoparticulate drug delivery system.
13

14. Types of NPDDS
Polymer Based Lipid Based Metal Based
Dendrimers Liposomes Metal Colloids
(1 – 10nm) (10 -100nm) (1 – 50nm)
Polymeric Micelles Solid Lipid Nanoparticles Carbon Nanotubes
(10 -100nm) (50 -400nm) (1 -10nm)
Niosomes Lipid Vesicles Fullerence
(10 -150nm) (1 -10nm)
Nanocapsules Gold Nanoshells
(100 – 300nm) (10 – 150nm)
Nanospheres Silicon nps
(1 – 15nm) (50 – 500nm)
14

15.  Nanotechnology in Chemotherapy
 Nanotechnology in Cancer
 Nanotechnology in Diabetes
 Nanotechnology in CVS Disorders
 Nanotechnology in CNS Disorders
 Nanotechnology in Tissue Repair & Regeneration
 Nanotechnology in Surgery
 Nanotechnology in Organ Transplantation
 Nanotechnology to Deliver Nutrition supplements
 Nanotechnology in cosmetics
 NPDDS for proteins and peptides
 Ocular applications of NPDDS
 NPDDS for pulmonary treatment
 NPDDS for central nervous system
15

16. Figure 3 : Applications of NPDDS 16

17.  both passive and active drug targeting after parenteral administration may be achieved.
 Achievement of increase in drug therapeutic efficacy and reduction in side effects.
 Controlled release and particle degradation characteristics can be readily modulated by the
choice of matrix constituents.
 Drug loading is relatively high and drugs can be incorporated into the systems without any
chemical reaction; this is an important factor for preserving the drug activity.
 Site-specific targeting can be achieved by attaching targeting ligands to surface of particles
or use of magnetic guidance.
 The system can be used for various routes of administration including oral, nasal, parenteral,
intra-ocular etc.
17

18.  Size of nanoparticles required
 Inherent properties of the drug , ex. Aqueous solubility
 Surface characteristics such as charge and permeability
 Degree of biodegradability, biocompatibility and toxicity
 Drug release profile desired
 Antigenicity of the final product 18

19.  Nanoparticles can be prepared by following methods;
1. Dispersion of preformed polymers
2. Polymerization of monomers
3. Ionic gelation or coacervation
4. Solvent evaporation
1. Dispersion
Dispersion of preformed polymers is a common technique used to prepare biodegradable nanoparticle.
poly (lactic acid) (PLA)
poly (D,L-glycolide)
PLG
poly (D,L-lactide-coglycolide) (PLGA)
poly(cyanoacrylate) (PCA)
19

20. Figure 4 : Dispersion method of Nanoparticles
2. Polymerisation
In this method, monomers are polymerized to form nanoparticle in an aqueous solution.
Drug is incorporated either by being dissolved in the polymerization medium or by adsorption onto the nanoparticles
after polymerization completed.
The nanoparticle suspension is then purified to remove various stabilizers and surfactants employed for polymerization
by ultracentrifugation and re-suspending the particles in an isotonic surfactant-free medium.
This technique has been reported for making polybutylcyanoacrylate or poly ( alkylcyanoacrylate) nanoparticles.
20

21. Figure 5 : Polymerisation Method of Nanoparticles
3. Ionic Gelation and Coacervation
The preparation of nanoparticles using biodegradable hydrophilic polymers such as chitosan, gelatin and sodium alginate.
Calvo and co-workers developed a method for preparing hydrophilic chitosan nanoparticles by ionic gelation.
In this method, positively charged amino-group of chitosan interacts with negative charged tripolyphosphate to form
coacervates with a size in the range of nanometer.
21

22. Figure 6 : Ionic
Gelation methods
of Nanoparticles
Figure 7 : Coacervation method of Nanoparticles
22

23. 4. Solvent Evaporation
•In this method, the polymer is dissolved in an organic as solvent such as dichloromethane, chloroform or ethyl acetate which
is also used the solvent for dissolving the hydrophobic drug.
•The mixture of polymer and drug solution is then emulsified in an aqueous solution containing a surfactant or emulsifying
agents to form an oil in water (o/w) emulsion.
•After the formation of stable emulsion, the organic solvent is evaporated either by reducing the pressure or by continuous
stirring.
•Particle size was found to be influenced by the type and concentrations of stabilizer, homogenizer speed and polymer
concentration.
•In order to produce small particle size, often a high-speed homogenization or ultrasonication may be employed.
Figure 8 : Solvent
Evaporation Method
of Nanoparticles
23

24. The polymeric drug carriers deliver the drug at the tissue site by any one of the three
general physicochemical mechanism.
By the swelling of the polymer nanoparticles by hydration followed by release through
diffusion
By an enzymatic reaction resulting in rupture or cleavage or degreadation of the
polymer at site of delivery, there by releasing the drug from the entrapped inner core
Dissociation of the drug from the polymer and its deadsorption/release from the swelled
nanoparticles.
The release of drug from the particulate system depends upon three different mechanisms :
 Release from the surface of particles.
 Diffusion through the swollen rubbery matrix.
 Release due to erosion.
24

25. In the majority of cases , drug release follows more than one type of mechanism.
•Diffusion
•Degradation
•Swelling followed by diffusion
1. Diffusion
Diffusion occurs when a drug or other active agent passes through the polymer that forms the controlled release device .
The diffusion can occur on a macroscopic scale – as through pores in the polymer matrix or on a molecular level , by passing
between polymer chains.
2. Swelling
Swelling controlled release systems are initially dry and when placed in the body , will absorb water or other body fluids and
swell . The swelling increases the aqueous solvent content wiithin the formulation as well as the polymer mesh size ,
enabling the drug to diffuse through the swollen network into the external environment .
3. Degradation
It take place in two ways ,
•Bulk eroding
•Surface eroding
25

26. In surface eroding systems , polymer degradation is much faster than the water imbibitions into the polymer bulk .
thus , degradation occurs predominantly within the outermost polymer layer. Erosion affect only the surface not the
inner parts of the system . bulk eroding polymers degrade slowly and the imbibitions of water into the system is
much faster than the degradation of the polymers.
Figure 9 : Various mechanism of drug release
26

27. Drug entrapment efficiency
Particle shape
Particle size
zeta potential
1. Drug entrapment efficiency
 The nanoparticles were separated from the aqueous medium by ultracentrifugation at 10,000 rpm for 30 min at
5c.
 Then the resulting supernatant solution was decanted and dispersed into phosphate buffer saline pH 7.4.
 Thus the procedure was repeated twice to remove the unentrapped drug molecules completely.
 The amount of drug entrapped in the nanoparticles was determined as the difference between the total amount of
drug used to prepare the nanoparticles and the amount of drug present in the aqueous medium.
27

28. 2. Particle Shape
•The nanoparticles were subjected to microscopic examination (SEM) for characterization size.
•The nanosuspension was characterized by SEM before going for evaluation; the nanosuspension was lyophilized to form
solid particles.
•The solid particles were coated with platinum alloy using a sputter coater.
3. Particle Size
•Particle size and size distribution are the most important characteristics of nanoparticle systems.
•They determine the in vivo distribution, biological fate, toxicity and targeting ability of nanoparticle system.
•In addition, they can also influence the drug loading, drug release and stability of nanoparticles.
•Currently, the faster and most routine method of determining particle size is by photon-correlation spectroscopy or
dynamic light scattering.
•The results obtained by photon-correlation spectroscopy are usually verified by scanning or transmission electron
microscopy (SEM or TEM).
28

29. 4. Zeta Potential
•The Zeta potential of a nanoparticle is commonly used to characterized the surface charge property of nanoparticles.
•It reflects the electrical potential of particles and is influenced by the composition of the particle and the medium in which it
is dispersed.
•Nanoparticles with a zeta potential above (±) 30 mV have been shown to be stable in suspension, as the surface charge
prevents aggregation of the particles.
29

30. 1.Kreuter, J.O. Historical Perspectives Nanoparticles-a historical perspective.Int.J.Pharm.,331;10,2007.
2. Kostarelos K. The emergence of Nanomedicine.,01; 1-3, 2006.
3. Mohanraj VJ , Y.C. Nanoparticles -A Review. Trop J Pharma Res. 05(01):56,573,2006.
4. Alagarasi A. Introduction to nanomaterials.2011.
5. Anne des Rieux a, b., Virginie Fievez a,b, Marie Garinot a, Yves-Jacques Schneider b, Véronique
Préat. Nanoparticles as potential oral delivery systems of proteins and vaccines: A mechanistic
approach. Journal of Controlled Release. 116;1-27,2006.
6. Crommelin, G.S.a.D.J.A. Liposomes: quo vadis? Elsevier Science Ltd. 01(01);19-31,1998.
7. Roger, A. Nanotechnology Applications for Drug Delivery, Drug Delivery
Nanotechnology.21-28,2004.
8. www.biosyn.com. Nanoparticles applications in biology and medicines . Access on 29 April 2019.
30

31. 9. Patil Y. Nanoparticles: smart drug delivery systems. Curr Trends Biomedical Eng & Biosci. 11(3);001-003.,2018.
10. Patra J k, Das G, et al. Nano based drug delivery : recent development and future prospects. J Nanobiotechnol.
1-33,2018.
11. Wang J, Xiongbin H, Daxiong X. Nanoparticle drug delivery system : an excellent carrier for tumor
peptide vaccines.25(1);1319-1327,2018.
12. Maleki A, Karimpour A R, Maleki S. The role of mechanicsl engineering in the development of nano
drug delivery systems; a review . Int J Nano Dimens.9(1);1-6,2018.
13. Karapussamy C, Venkatesan P. Role of nanoparticles in drug delivery system : a compreshensive
review . J Pharm Sci & Res. 9(3); 318-325, 2017.
14. Anees M, Masood I, Ilyas m, Hussain T, Ahmad M. Nanoparticle as a novel drug delivery
system : a review. Pak J Pharm Sci. 02; 160-167, 2016.
15. Sriharitha, Preethi J, Hemanth S. A review on nanoparticles in targeted drug delivery system. J.
Mater .Sci. 4; 1-6, 2014.
16. Sagadevan S, Periasamy M. A review on role of nanostructures in drug delivery system. Red Adv
Mater Sci. 36;112-117,2013
31

32. 17. Kalpesh C, Jalpa S, Soniwala M, chavada J.R, Badjatiya J.K. Nanoparticulate drug delivery
system : a novel approach. Int J Drug Regul Aff. 2; 39-48 , 2013.
18. Kaur P, Kaur L, Khan M. Nanoparticles as a novel drug delivery system: a review. Int J Res Phar
& Chem. 2(3); 756-760,2012.
19. Jawahar N, Meyyanathan S. Polymeric nanoparticles for drug delivery and targeting : a
compreshive review. Int J Health Allied Sci.1; 217-233, 2019.
20. Singh S, Pandey V, Tewari R, Agrawal V. Nanoparticle based drug delivery system: advantages
and applications. Indian J Sci Technol. 4; 177-180, 2011.
21. Shakywar Y, Dwivedi S, Gupta S, Jain A. A comprehensive review on nanoparticle drug delivery
system. 2011.
22. Peter HM , I.B.-H., Oleg V , Nanoparticles – known and unknown health risks. J
Nanobiotechnology, 02(12): 0115, 2004.
23. Velavan P, Karrupusamy C, Venkatesan P. Nanoparticles as drug delivery system. J Pharm Sci &
Res. 7(12);1118-1122,2015.
24. Ranghar S, Sirohi P, Verma P, Agrawal V. Nanoparticles – based drug delivery system : promising
approaches against infections. Braz arch biol technol .57;2014.
32

33. 25. Crommelin D. Liposomes : vesicles for the targeted and controlled delivery of peptides and proteins
. J Controlled Release.46;165-175,1997.
26. Union E. Nanomedicine technology for health European platform strategic research agenda for
nanomedicines. Ed E Union. European Union . 2006.
27. Wagnar A. Liposomes produced in pilot scale : production purification and efficiency aspects. Eur J
Pharm Biopharm. 54;213-219,2002.
28. Shaji J. Immunoliposomes : targeted delivery foe cancer. Pharma Times . 39;17-20, 2007.
29. www.mangeshshahblog.webpin.com . what are some amazing applications of nanoparticles in the
field of medicine? Access on 30 April 2019.
30. Rolland J., Maynor B., Eullis L., Exner A., Denison G., Direct fabrication and harvesting of
monodispersed shape specific nonobiomaterails ., J Am Chem Soc.,127; 10096-10100., 2005.
31. Badjatya J.K, R.B. Enhancement of Dissolution of Poorly Water Soluble Aceclofenac by preparing
Nanoparticles Inventi Rapid:NDDS. 2012(01);01-02, 2012.
32. Dr. Mohmmed Ali, D.A.A.S., Showkat R. Mir, A Wadood S. GPAT : A Ideal book for Pharmacy
Competative Exams. Delhi: Birla Publications Pvt. Ltd. 5.30.2'nd ed. 01; 2012.
33. Moghimi, S.M. Particulate nanomedicines. Adv. Drug Deliv. 58;1451-1455,2016.
33

34. 34. Ramin A, Kaur S, Rao S. Intertechnique comparison for nanoparticles size measurement and shape
distribution. J Hazard Toxic Radioact Waste. 20(1);2016.
35. Tyagi S, Pandey V.K. Nanoparticles : overview preparation. J Pharm & Nanotech. 2016.
36. Tyagi S, Pandey V.K. Nanoparticles : overview preparation. J Pharm & Nanotech. 2016.
37. Dr. Manjanna K. M. , Kumar P. Microencapsulation : an acclaimed Novel Drug Delivery Systems for
NSAIDs in Arthritis. 27(6);501-532,2010.
38. Sharma N, Purwar N, Gupta P. Microspheres as drug carrier for controlled drug delivery : a review.
Int J Pharm Sci Res.6(611),4579-4587,2015.
39. Keoil R, Pagel m, Muldoon l, et al. Improving drug delivery intracerabletumor and surrounding
brain in a rodent model ;comparison of osmotic and bradikinin modification of blood tumor
barrier.Neurological.43; 879-886.,1998.
40. kreuter J, Ramage P, Hamm S, et. al. Direct evidence that polysorbate -80 coated
poly(butylcynoacrylate) nanoparticles deliver drugs to the CNS via specific machanisms required
prior binding of drug to the nanoparticles . Pharm Res . 20;409-16., 2003.
41. Puglisi G, Fresta M, Giamonna G, Ventura C. Influence of preparation conditions on
poly(ethylcynoacrylate) nanocapsules formation . Ind J Pharm. 125; 283-287., 1995.
42. Couvreur P, Barratte G, Fattal E, Legrand P, Vanthier C. Nanocapsule technology : a review . Crit
Res Thur Drug Carrier Syst. 19 ;99-134,2002.
34

35. 43. Badjatya J.K, R.B. Enhancement of Dissolution of Poorly Water Soluble Aceclofenac
by preparing Nanoparticles Inventi Rapid:NDDS. 2012(01): 01-02, 2012.
44. Kompella U., Bandi N., Ayalasomayajula S., Poly(lactic acid) nanoparticles for sustained release of
bubesonide ., Drug Deliv Technol.,1; 1-7., 2001.
45. Moghimi, S.M. Particulate nanomedicines . Adv. Drug Deliv. 58; 1451-1455,2006.
46. Lee HJ. Protein drug oral delivery: The recent progress. Arch Pharm Res. 25 (5);572-
584, 2002.
47. Torchlin VP. Drug Targeting. Eur J Pharm Sci ; 11 (Suppl.2);S81-S91,2012.
48. Dr. Ali M., D.A.A.S., Showkat R. M., Siddiqui A W, GPAT : A Ideal book for Pharmacy
Competative Exams. 2'nd ed. GPAT : A Ideal book for Pharmacy
Competative Exams.01., Delhi: Birla Publications Pvt.Ltd. 5.30, 2002.
49. Zhang Q, Shen Z, Nagai T. Prolomg hypoglycemic effect of insulin loaded polybutylcynoacrylate
nanoparticles after pulmonary administration to normal rats. Int J Pharm. 218;75-80.,2001.
50. Bounded H, Legrand P, Lebas G, Cheron M, et.al. Nanoparticles intended for oral administration
of sequinarvir, Ind J Pharm . 218;113-124, 2001.
51. Pulgisi G., Fresta M., Gimmina G., Ventura C., Influence if insulin preparation on
poly(ethylcynoacrylate) nanocapsule formation ., Ind J pharma., 125;283-287., 1995.
52. Calvo P., Remunan C., Vila J., Alonso M., Novel hydrophilic chitosan polyethyelene oxide
nanoparticles as protein carrier., J Appl Polymer Sci., 63;125-132,1997.
53. Li Y., Pei Y., Zhou Z., Zhang X., Gu Z.,Nanoparticles as tumor necrosis factor –[alpha] carriers., J
Control release ., 71; 287-296., 2001. 35