JBNB  Vol.7 No.2 , April 2016
Effects of Size and Surface Charge of Polymeric Nanoparticles on in Vitro and in Vivo Applications
ABSTRACT
Biodegradable polymeric materials are the most common carriers for use in drug delivery systems. With this trend, newer drug delivery systems using targeted and controlled release polymeric nanoparticles (NPs) are being developed to manipulate their navigation in complex in vivo environment. However, a clear understanding of the interactions between biological systems and these nanoparticulates is still unexplored. Different studies have been performed to correlate the physicochemical properties of polymeric NPs with the biological responses. Size and surface charge are the two fundamental physicochemical properties that provide a key direction to design an effective NP formulation. In this critical review, our goal is to provide a brief overview on the influences of size and surface charge of different polymeric NPs in vitro and to highlight the challenges involved with in vivo trials.

Received 15 October 2015; accepted 19 April 2016; published 22 April 2016

1. Introduction

Manufacturing effective drug delivery system is a critical challenge in nanomedicine since nanocarriers are expected to reach and accumulate in the site of interest. As a consequence, numerous drug delivery systems have been investigated in vitro and in vivo to deliver a wide range of drugs and molecules. To conquer the challenge, with the aim of avoiding uncontrolled biodistribution, rapid clearance and systemic toxicities in healthy tissues polymeric nanoparticles (NPs) have gained higher interest among all the novel formulations. Research during the past few decades proves their beneficial features in formulation design, characterization, behavior and application [1] . The in vitro and in vivo fate of NPs is particularly depended on uniformity of particle size and zeta potential. Change in these properties has significant biological implications on cellular internalization, pharmacokinetics, and bio-distribution [2] . These characteristics of NPs facilitate the opportunities for therapeutic application, which can be confirmed by in vitro and in vivo studies [3] . The aim of most nano-devices is to prevent the degradation of drug followed by higher bioavailability in cellular level and to regulate its pharmacodynamics profile. Thus, the nanomedicine platforms could serve as a drug delivery system that is able to transport a high dose of therapeutics selectively to the desired site of action. Although very few investigations have been performed, most of the articles related to exploring the effects of size and surface charge of NPs have been discussed in this review. This review provides details on the fate of different polymeric NPs and will discuss how the size and surface charge of polymeric NPs are involved in desired effects for both in vitro and in vivo applications. Moreover, other polymeric NPs using various preparation methods have been also summarized in Table 1, which could be considered for further size and surface charge related experiments.

Table 1. Size and surface charge overview of different polymeric NPs.

Abbreviation: BCEC: Brain capillary endothelial cells; BSA: Bovine Serum Albumin; DCs: Dendritic Cells; HASMCs: Human arterial smooth muscle cells; HA-VSMCs: Human aortic vascular smooth muscle cells; HMSCs: Human mesenchymal stem cells; HUVECs: Human umbilical vein endothelial cells; MOEC: Murine ovarian endothelial cells; NAcHis-GC: N-acetyl histidine conjugated glycol chitosan nanoparticles); P (MDS-co-CES): Poly (methyldiethene-aminesebacate)-co-[(cholesterylox-ocarbonylamidoethyl) methylbis (ethylene) ammonium bromide] sebacate; PBMCs: Peripheral blood mononuclear cells; PBS: Phosphate buffer saline; PEG: Poly (ethylene glycol); PEG-PHDCA: Poly (methoxypolyethyleneglycol cyano- acrylate-co-hexadecylcyanoacrylate); PEMA: Poly (ethylene-maleic anhydride); PEO-b-PMA: Poly (ethylene oxide)-b-poly (methacrylic acid); PLA: Poly (lactic acid); PMB: Poly [2-methacryloyloxyethyl phosphorylcholine (MPC)-co-n-butyl methacrylate (BMA); PMBH: Poly [2-methacryloy- loxyethyl phosphorylcholine (MPC)-co-n-butyl methacrylate (BMA)-co-methacryloylhydrazide (MH)]; PVA: Polyvinyl Alcohol; RBECs: Rat brain endothelial cells; TPGS: Tocopheryl polyethylene glycol succinate; VSMCs: Vascular smooth muscle cells; WGA: Wheat germ agglutinin.

2. Polymeric NPs

For an ideal drug delivery system, recognition of the polymer’s potentiality has been evaluated since 1960’s [4] . Over the past few decades, two main classifications of polymers have been discovered as synthetic and natural, each with various types and sub-types. Synthetic polymers are chemically synthesized based on repeated structural units, whereas natural polymers are obtained from natural sources. Primarily two types of polymeric NPs have been developed for drug delivery purposes i.e. nanocapsules, in which a core of encapsulated drug is surrounded by polymeric membrane or shell; and nanospheres, where drug is distributed/adsorbed throughout a matrix [5] . The most important feature of polymers is the degree of biodegradability, which is an important criterion to differentiate some slowly biodegradable polymers such as polystyrene (PS), poly (cyanoacrelates) (PCA), polyethylenimine (PEI) and poly (methyl methacrylate) (PMMA) [6] - [11] . On the other hand, some synthetic polymers such as poly (ɛ-caprolactone) (PCL), poly (lactide) (PL), poly (glycolide) (PGA), poly (D, L-lactide-co-glycolide) (PLGA), and some non-synthetic polymers (e.g. chitosan) are categorized as readily biodegradable materials [12] - [16] . Polymeric NPs are capable to maintain high stability in systemic circulation with enhanced half-life, which can be further optimized by controlling the release of therapeutic agents from the NPs. Moreover, polymeric molecules have various solubility profiles in wide range of solvents. This is advantageous for surface modification or functionalization to achieve different purposes of delivery and targeting. Subsequently, both doses and frequency of administration of therapeutic agents can be reduced due to high payloads into nanocarriers, leading to superior efficacy and minimizing the side effects. Besides, polymeric NPs of desired physicochemical properties are capable of preserving their content from hepatic metabolism, enzymatic degradation and rapid clearance. Specifically, the enormous surface area of polymeric NPs is an attractive feature to control the release kinetics, drug loading capacity and administration route, which can regulate the fate of drug into the body [17] . However, only few of them have been approved by health regulatory agencies for human trial to apply for carrying a wide range of diagnostic and therapeutic agents to the desired site of action [18] .

3. Effect of Particle Size and Surface Charge Based on in Vitro Studies

Different types of NPs have been widely applied as drug delivery vehicles for diagnostic and targeted therapy (active or passive) to achieve maximum cellular uptake and therapeutic bioavailability [19] [20] . Continuous physicochemical changes in the development of polymeric NPs may have substantial implications in the cellular internalization and biological processes [21] . The experiments performed to evaluate the influence of particle size and surface charges of NPs are expected to explain how these physicochemical properties influence the cell uptake through various pathways towards optimum biodistribution.

Cellular internalization or uptake is the most important physicochemical criteria prior to in vivo application. Uptake of small molecules by any cells depends mainly on endocytosis among all other mechanisms (Figure 1). Endocytosis is the bulk active transport process through lipid bilayer wrapping using energy in the form of ATP to form required vesicles. Two main endocytosis mechanisms are reported as phagocytosis and pinocytosis [22] . Phagocytic cells (e.g. macrophages, neutrophils, dendritic cells, etc.) mediated cellular internalization is mostly involved with engulfing the large particles (>1 µm) [23] . Adsorption or receptor dependent internalization is the main mechanism of pinocytosis, which is mainly related to particle uptake by the cells through different pathways such as macro-pinocytosis, clathrin mediated, caveolin dependent or independent pinocytosis [3] . Size and surface charge of polymeric NPs are likely the preliminary physicochemical variables, which govern the endocytosis dependent cellular uptake. Besides, positive charge of the surface of polymeric NPs may endorse more cellular attachment causing higher uptake either by endocytosis or by direct penetration, since cationic surface of polymeric NPs interacts with anionic terminal of phospholipid, proteins and glycans on the cell surface due to the electrostatic interactions [23] .

An interesting experiment by Bhattacharjee et al. demonstrated the effects of size and surface charge of fluorescent, monodisperse tri-block co-polymeric NPs based on cellular uptake through different endocytotic pathways [24] . They synthesized polymeric NPs (PNPs) with two different sizes (45 and 90 nm) and surface charges such as neutral (PNP-OH, −4 mV), positive (PNP-NH2, +22 mV) and negative (PNP-COOH, −19 mV) to observe the in vitro cellular uptake into NR8383 (rat macrophage) and Caco-2 (human colonic adenocarcinoma) cells. For size dependent cellular uptake, a relative uptake study was carried out, which revealed the higher

intracellular uptake by positively charged polymeric NPs with lower size compared to the other formulations.

Figure 1. Relative sizes of NPs favorable for ingestion through various endocytotic pathways.

Inhibition of endocytic pathways was adopted to observe the role of endocytosis based cellular internalization of polymeric NPs tracked by two mechanisms such as decreasing temperature to 4˚C of experimental unit and exposing cells with 2-deoxyglucose (2-dOG) and sodium azide (NaN3). Both inhibitory approaches showed considerably lower uptake, which proved the higher uptake by positive charged polymeric NPs compared to that of neutral to more negative charged polymeric NPs. Followed by the same strategy to block the clathrin and caveolin mediated endocytosis, cells were exposed with hypertonic 450 mM sucrose solution and methyl-beta-cyclo- dextran, respectively. Meeting the claimed fenestration sizes of these receptors dependent endocytosis, both inhibitions resulted with reduced uptake with smaller size after treating these cells with polymeric NPs, however the uptake was varied with charge variations. For clathrin dependent endocytosis, uptake by both neutral and negatively charged polymeric NPs was higher (65% and 75%, respectively) than positively charged polymeric NPs (less than 38%), however an opposite result was found for caveolin dependent endocytosis.

On the other hand, Lai et al. investigated that polystyrene (PS) NPs with smaller size (>42 nm) were successfully internalized into HeLa cells following clathrin and caveolin independent endocytic pathways avoiding endosomal or lysosomal accumulation [25] . Recent studies revealed that positively charged NPs uptake was related to energy dependent process such as proteins dynamin and F-actin but negatively charged NPs were not dependent on dynamin proteins around the cell membrane [26] . Moreover, highly positively-charged NPs could cause perforations in the cellular lipid bilayer to enter the cells by-passing endocytic pathways [23] .

Another in vitro study for both fluorescent PS NPs and Coumarin-6 NPs in Caco-2 cells by Win et al. was performed to assess the effects of different polymeric NPs size [27] . Raw Coumarin-6 could not increase the cell uptake, however fluorescent PS NPs of 100 nm to 200 nm size showed the highest percentage of uptake. Smaller particles (50 nm) showed the lowest uptake and particles as large as 1000 nm showed decrease in uptake, which could be attributed to the uptake by other cellular mechanisms.

Optimization of antigen delivery to human dendritic cells (DCs; antigen presenting cells) is a challenge for advanced vaccine delivery systems. To identify the effects of particle size and surface charge on human DCs, in vitro cell uptake study has been investigated by Foged et al. in 2005 [28] . They designed the experiment based on wide size ranges (0.1 µm to 4.5 µm) of fluorescent PS NPs with different surface charges (+12.4 to −66.9 mV) after surface modification. Flow cytometric analysis of DCs after 24 hour incubation showed that lower percentage of DCs had taken up 4.5 µm particles (30%); whereas the highest cellular uptake (60%) was observed for 0.5 µm and 0.1 µm sized particles. To optimize the charge dependent interactions, particles with two sizes (0.1 and 1 µm) were modified by attaching variety poly amino acids/proteins covalently utilizing surface amine and carboxyl groups. Sterically same positive and neutral charges particles were obtained using polypeptides poly-l-lysine (PLL) and poly-d-l-alanine (PA), respectively. After 24 hours incubation, only 10% cellular uptake was observed with negatively charged 1 µm size particles, whereas positive charged particles were accounted for 60% uptake. However, around 90% uptake was observed for lower size (0.1 µm) particles with positive charge.

Prior to in vivo administration, it is essential to consider the compatibility, safety and biodegradability of the particles with the human blood and cells. To investigate the efficiency of particle size and surface charge in in vitro cellular uptake and blood compatibility, recently Dash et al. employed chitosan/polyglutamic acid hollow spheres to treat human umbilical vein endothelial cells (HUVECs) and human umbilical artery smooth muscle cells (HUASMCs) [21] . Enhanced cellular uptake has been observed with 100 nm neutral charged (−4 mV) in both cells such as 76% in HUVECs and 56% in HUASMCs compared to the other larger as well as pegylated particles regardless of surface charge. However, negatively charged particles showed the least cell internalization in both cases. To measure the effects of particles with erythrocytes of human blood, percentage of hemolysis was accounted towards different sizes and charges of particles. All types of particles were partially associated with very insignificant consequence on hemolysis (1% or less) without considering either size or surface charge. But, highly anionic charged particles of smaller size resulted insignificant delayed clotting time and platelet activation profile compared to larger particles and other types of charged particles.

Testing blood compatibility of polymeric NPs with human blood is another way for finding the probable adverse effects, which may happen after in vivo administration. To rationalize the hemo-compatibility test, another research group (Mayer et al.) employed PS NPs with variety of sizes and surface charges in different mediums (such as cell culture medium with different FBS ratio, PBS) [29] . To assess the influence of polymeric NPs’ size and surface charge on human blood, the aim of study was to monitor the adverse effects by measuring complement activation, induction of coagulation, thrombocyte activation, membrane integrity, granulocyte activation, and hemolysis using flow cytometric analysis. Complement (C3a and C5a) levels detection is a consideration of the body’s immune system activation. Cationic amidine PS particles were involved with high C3a generation (150.8%). Irrespective to size and surface charge, no NPs were involved with prothrombin level induction. CD62P/CD42b labelling was employed to investigate the thrombocyte activation, which was tested for both low (0.5 mg/mL) and high (2 mg/mL) concentrations. But no thromocytic damage was observed, which were confirmed by no lactate-de-hydrogenase (LDH) release for any of the particles. The percentage of CD11b expression (marker for granulocyte activation) for particle’s different sizes and surface charges was reported in that study. Increased percentage of hemolysis for all types of particles was reported using high concentration of particle treatment with human blood. However, larger particles were found less hemolytic than smaller particles, and the most important point was that no influence was observed for negatively charged 160 nm size NPs on erythrocytes of human blood by treating with lower concentration. Overall, positively charged larger particles were involved with more hemolysis compared to negatively charged particles and the latter ones larger than 60 nm size appeared to be less hematotoxic than smaller particles. One interesting finding was; particles resuspended in cell culture medium with 10% fetal bovine serum (FBS) showed less negative zeta potential or about to close to neutral charge compared to the particles resuspended in phosphate buffer saline (PBS). The presence of salts and proteins in the dispersion cell medium might be accountable for neutralizing surface charge of polymeric NPs.

Upon exposure of different types of PLGA NPs to different experimental media, Mura et al. also investigated the possible size and zeta potential variations after resuspension of polymeric NPs in different media with time dependent incubation up to 96 hours at 37˚C [30] . Three types of medium such as water, cell culture medium plus 10% FBS and PBS have been considered for evaluation in this experiment. Among different media, water and cell culture medium containing 10% FBS were not involved with significant variations in particle size regardless of surface charge, however after incubation of PLGA/chitosan (CS) NOS in PBS the size was increased. Furthermore, upon exposure to serum containing cell culture medium, PLGA/CS, PLGA/polyvinyl alcohol (PVA), and PLGA/pluronic F-68 (PF-68) NPs did not show any noteworthy change in zeta potential values.

They also designed in vitro model to investigate the toxicity of these prepared three types of NPs with Calu-3 cell line derived from human bronchial adenocarcinoma. This cell line could be a representative bronchial epithelial barrier associated with the discharge of airway mucus substances and the moderation of inflammatory reaction [31] [32] . Cell viability responses due to NP treatment with higher concentration after 72 hours incubation demonstrated that only PLGA/PF68 NPs showed progressively decreased cell viability compared to other types of NPs.

From other in vitro studies, it has also been found that NPs with 40 - 50 nm size range are involved with maximum uptake [33] [34] . However, a recent experiment by Schadlich et al. revealed the effect of size for the accumulation of near-infrared (NIR) fluorescent consisting PLA-PEG polymeric NPs in two tumor xenograft models (HT29 colorectal carcinoma and A2780 ovarian carcinoma) utilizing in vivo fluorescence imaging technique [35] . NPs of 111 nm and 141 nm size showed higher biodistribution and accumulation in tumors compared to the larger size (166 nm), which was due to rapid clearance of the larger particles by liver.

4. Effect of Particle Size and Surface Charge Based on in Vivo Studies

To explore the in vivo effects of specifically sized NPs with respect to surface charge, Kulkarni et al. injected the fluorescent modified and unmodified PS NPs into Sprague?Dawley rats after physicochemical characterization [36] . Modification of PS NPs was performed by coating with D-α-tocopheryl polyethylene glycol succinate or Vitamin E TPGS, which was able to switch the zeta potentials of different size NPs to less negative charge.

As previously known, circulating mononuclear phagocytic cells in the bloodstream are the key component of reticuloendothelial system (RES). In addition, RES is also composed of matured cells such as macrophages mainly available in lungs, liver and spleen [37] . Studies have shown that the NPs with the size range of 100 to 200 nm could be the optimum range in order to escape the RES recognition [27] . Due to rapid clearance from systemic circulation, mostly uncoated NPs were distributed to those organs such as liver and spleen, where mononuclear phagocytic system is located. Consequently, 100 and 200 nm size fluorescent PS-TPGS NPs resulted in higher fluorescence concentration in blood plasma regardless of their surface charges. Liver and spleen were the main target organs, where a substantial decrease in NP distribution was observed for all sizes of TPGS modified PS NPs, since hydrophilic coated surface (stealth effect) possesses the ability to prevent the NPs from RES capture.

Moreover, He et al. in 2010 investigated the effects of size and surface charges on the biodistribution of different sizes of rhodamine B (RhB) labeled carboxymethyl chitosan grafted NPs (RhB-CMCNP) and chitosan hydrochloride grafted NPs (RhB-CHNP) having negative and positive surface charges after intravenous administration into H-22 tumor bearing mice [2] . It was clearly demonstrated that biodistribution of 150 nm size NPs having zeta potential of around −15 mV showed higher accumulation at the tumor site and long residence in blood compared to more negative or positive or even larger particles. Due to inflammation and disorder of endothelium along with high demand of nutrient supply, comparatively larger vascular leakage is found in solid tumors, which can provide more access for extravascular targeting macromolecules [38] . Low anionic charge (−15 mV) bearing RhB-CMCNP-PS particles exhibited higher percentage of distribution in tumor, which might be due to enhanced residing time during systemic circulation [39] . On the other hand, more positive charged NPs could leave the interstitium more competently after arriving the tumor’s leaky vasculature leading to be up taken by tumor cells or endothelium adjacent to the endothelium [40] . This phenomenon might be the possible reason why high cationic charge (+35 mV) bearing RhB-CHNP particles showed higher percentage of distribution in tumor. Due to enhanced permeability and retention (EPR) effects, smaller particles might be favorable to target the tumor passively due to higher accumulation. However, blood’s complement activation system and blood opsonins have been found to fabricate the size of polymeric NPs to a larger extent (>500 nm) resulting rapid blood clearance [39] . RhB-CMCNP and RhB-CHNP with larger particle size resulted in higher hepatic disposition. Such higher hepatic disposition could be explained by the investigation performed by Liu et al. They found that NPs with the size range above 300 nm were inclined to be blocked or captured by RES as well as liver sinusoids [41] . In addition, NPs with the size range from 200 to 500 (nm) was found mainly unaffected by the splenic physical filtration mechanism [42] . This could be attributed to obtain lower percentage of hepatic distribution of RhB-CHNP NPs with the particle size range from 150 to 300 (nm). Besides, no influence was observed in distribution of both RhB-CMCNP and RhB-CHNP particles in kidney owing to their size and surface charge. Due to electrostatic reactivity, positively charge particles had tendency to form aggregates with the cells and proteins present in blood and subsequently the aggregation could be trapped by lung [43] . As this experiment revealed, He et al. demonstrated the similar result where more cationic RhB-CHNP NPs distribution was found in lung.

NPs of 10 - 100 nm size is considered as mainly accepted range to design any NP formulation respective to suitable clearance and biodistribution profile before any in vivo trial [3] . However, the upper range of particle size is dependent on the interactions with body’s immune systems and the lower range is determined by the limit of kidney filtration. Opsonization of larger particles by responsible proteins (e.g. plasma complement, immunoglobulins) in blood compartment is common to develop hypersensitivity response comparatively against larger foreign particles [44] [45] . On the other hand, smaller particles (<5.5 nm) have been found with rapid clearance from the body by kidney’s glomerular filtration mechanism [46] .

To explore the in vivo effects of different size of NPs, Liu et al. prepared radioisotope labeled liposomes of different sizes (30 - 400 nm) to inject into the mice models to observe the biodistribution in blood, liver, spleen, and tumor [47] . After four hours of post administration, it was found that about 60% of 100 to 200 nm size particles were found in blood, but only 20% of injected particles with size boundary (>250 nm or <50 nm) were detected in blood. In liver, particle size with 100 nm was associated with 20% accumulation, whereas around 25% distribution in liver was detected for larger particles. In spleen, 40% - 50% of the injected dose was detected for larger size (>250 nm) but the percentage of detection was lower for the particle size range below 100 nm. In 2002, Levchenko et al. prepared liposomes of around 200 nm with variety of charged surfaces to evaluate the tissue distribution in mice models [48] . The results from this study showed that the negatively charged liposomes with zeta potential of around −40 mV were involved with higher clearance rate from the blood in comparison to liposomes with neutral zeta potential.

In addition, Yamamoto et al. investigated the effect of surface charge of poly (ethylene glycol)-poly (D, L-lactide) block copolymer micelles after injecting into male C57/BL6N mice through the tail vein [49] . They prepared the micelles with both neutral (tyrosine) and negative (tyrosineglutamine) functionalities, which did not show any significant variations in blood clearance kinetics. However, the negatively-charged micelles displayed a significant lower distribution in both liver and spleen after four hours of post intravenous injection. Overall effects of NPs size and surface charge could be summarized in Figure 2.

5. Conclusion

In conclusion, polymeric NPs with size range from 10 to 200 nm might not only escape renal filtration and biliary excretion but also accumulate in tumor utilizing EPR effects. Size range above 200 nm may be related to rapid hepatic clearance and RES recognition. Pegylation strategy could be an ideal option to stealth the poly- meric NPs for longer residing time during systemic circulation. After in vivo administration of cationic

Figure 2. Relative biocompatibility of polymeric NPs based on the effects of size and surface charge. Abbreviation: MPS (Mononuclear Phagocyte System), RES (Reticuloendothelial System), EPR (Enhanced Permeability and Retention).

polymeric NPs, non-specific interaction may occur with non-specific cells or opsonizing protein in blood compartment due to electrostatic bindings, which may involve unexpected cytotoxicity. In order to reduce such non- specific surface reactivity or interaction, relatively less negatively charged anionic (almost neutral) polymeric NPs with desired small size might be more rationale than cationic charged particles for a broad spectrum biological aspect. This review will help researchers to correlate the in vitro and in vivo effects of polymeric NPs based on particle size and charge. Further investigation and correlation of other physicochemical parameters could be performed on polymeric NPs to understand their biological effects.

Acknowledgements

This work was funded by a research grant from the Canadian Breast Cancer Foundation (CBCF) and Natural Sciences and Engineering Research (NSERC) Discovery Grant. The authors report no declarations of interest.

Conflict of Interest

The authors confirm that this article content has no conflict of interest.

NOTES

*Corresponding author.

Cite this paper
Sadat, S. , Jahan, S. and Haddadi, A. (2016) Effects of Size and Surface Charge of Polymeric Nanoparticles on in Vitro and in Vivo Applications. Journal of Biomaterials and Nanobiotechnology, 7, 91-108. doi: 10.4236/jbnb.2016.72011.
References
[1]   Grottkau, B.E., Cai, X., Wang, J., Yang, X. and Lin, Y. (2013) Polymeric Nanoparticles for a Drug Delivery System. Current Drug Metabolism, 14, 840-846.
http://dx.doi.org/10.2174/138920021131400105

[2]   He, C., Hu, Y., Yin, L., Tang, C. and Yin, C. (2010) Effects of Particle Size and Surface Charge on Cellular Uptake and Biodistribution of Polymeric Nanoparticles. Biomaterials, 31, 3657-3666.
http://dx.doi.org/10.1016/j.biomaterials.2010.01.065

[3]   Wang, J., Byrne, J.D., Napier, M.E. and DeSimone, J.M. (2011) More Effective Nanomedicines through Particle Design. Small, 7, 1919-1931.
http://dx.doi.org/10.1002/smll.201100442

[4]   Kleber, J.W., Nash, J.F. and Lee, C.C. (1964) Synthetic Polymers as Potential Sustained-Release Coatings. Journal of Pharmaceutical Sciences, 53, 1519-1521.
http://dx.doi.org/10.1002/jps.2600531219

[5]   Singh, R. and Lillard Jr., J.W. (2009) Nanoparticle-Based Targeted Drug Delivery. Experimental and Molecular Pathology, 86, 215-223.
http://dx.doi.org/10.1016/j.yexmp.2008.12.004

[6]   Lamprecht, A., Schafer, U. and Lehr, C.M. (2001) Size-Dependent Bioadhesion of Micro- and Nanoparticulate Carriers to the Inflamed Colonic Mucosa. Pharmaceutical Research, 18, 788-793.
http://dx.doi.org/10.1023/A:1011032328064

[7]   Behrens, I., Pena, A.I., Alonso, M.J. and Kissel, T. (2002) Comparative Uptake Studies of Bioadhesive and Non- Bioadhesive Nanoparticles in Human Intestinal Cell Lines and Rats: The Effect of Mucus on Particle Adsorption and Transport. Pharmaceutical Research, 19, 1185-1193.
http://dx.doi.org/10.1023/A:1019854327540

[8]   Galindo-Rodriguez, S.A., Allemann, E., Fessi, H. and Doelker, E. (2005) Polymeric Nanoparticles for Oral Delivery of Drugs and Vaccines: A Critical Evaluation of in Vivo Studies. Critical ReviewsTM in Therapeutic Drug Carrier Systems, 22, 419-464.
http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.v22.i5.10

[9]   Graf, A., McDowell, A. and Rades, T. (2009) Poly(alkylcyanoacrylate) Nanoparticles for Enhanced Delivery of Therapeutics—Is There Real Potential? Expert Opinion on Drug Delivery, 6, 371-387.

[10]   Vinogradov, S.B.E. and Kabanov, A. (1999) Poly(ethylene glycol)-polyethyleneimine NanoGelTM Particles: Novel Drug Delivery Systems for Antisense Oligonucleotides. Colloids and Surfaces B: Biointerfaces, 16, 291-304.

[11]   Plapied, L., Duhem, N., Rieux, A.D. and Préat, V. (2011) Fate of Polymeric Nanocarriers for Oral Drug Delivery. Current Opinion in Colloid & Interface, 16, 228-237.
http://dx.doi.org/10.1016/j.cocis.2010.12.005

[12]   Ahlin, P., Kristl, J., Kristl, A. and Vrecer, F. (2002) Investigation of Polymeric Nanoparticles as Carriers of Enalaprilat for Oral Administration. International Journal of Pharmaceutics, 239, 113-120.
http://dx.doi.org/10.1016/S0378-5173(02)00076-5

[13]   Kumari, A., Yadav, S.K. and Yadav, S.C. (2010) Biodegradable Polymeric Nanoparticles Based Drug Delivery Systems. Colloids and Surfaces B: Biointerfaces, 75, 1-18.
http://dx.doi.org/10.1016/j.colsurfb.2009.09.001

[14]   Song, X., Zhao, X., Zhou, Y., Li, S. and Ma, Q. (2010) Pharmacokinetics and Disposition of Various Drug Loaded Biodegradable Poly(Lactide-Co-Glycolide) (PLGA) Nanoparticles. Current Drug Metabolism, 11, 859-869.
http://dx.doi.org/10.2174/138920010794479682

[15]   Chaudhury, A. and Das, S. (2011) Recent Advancement of Chitosan-Based Nanoparticles for Oral Controlled Delivery of Insulin and Other Therapeutic Agents. AAPS PharmSciTech, 12, 10-20.
http://dx.doi.org/10.1208/s12249-010-9561-2

[16]   Liu, Z., Jiao, Y., Wang, Y., Zhou, C. and Zhang, Z. (2008) Polysaccharides-Based Nanoparticles as Drug Delivery Systems. Advanced Drug Delivery Reviews, 60, 1650-1662.
http://dx.doi.org/10.1016/j.addr.2008.09.001

[17]   Hu, C.M., Fang, R.H., Luk, B.T. and Zhang, L. (2013) Polymeric Nanotherapeutics: Clinical Development and Advances in Stealth Functionalization Strategies. Nanoscale, 6, 65-76.
http://dx.doi.org/10.1039/C3NR05444F

[18]   Kamaly, N., Xiao, Z., Valencia, P.M., Radovic-Moreno, A.F. and Farokhzad, O.C. (2012) Targeted Polymeric Therapeutic Nanoparticles: Design, Development and Clinical Translation. Chemical Society Reviews, 41, 2971-3010.
http://dx.doi.org/10.1039/c2cs15344k

[19]   Mundargi, R.C., Babu, V.R., Rangaswamy, V., Patel, P. and Aminabhavi, T.M. (2008) Nano/Micro Technologies for Delivering Macromolecular Therapeutics Using Poly(D,L-Lactide-co-Glycolide) and Its Derivatives. Journal of Controlled Release, 125, 193-209.
http://dx.doi.org/10.1016/j.jconrel.2007.09.013

[20]   Dinarvand, R., Sepehri, N., Manoochehri, S., Rouhani, H. and Atyabi, F. (2011) Polylactide-co-Glycolide Nanoparticles for Controlled Delivery of Anticancer Agents. International Journal of Nanomedicine, 6, 877-895.
http://dx.doi.org/10.2147/IJN.S18905

[21]   Dash, B.C., Rethore, G., Monaghan, M., Fitzgerald, K., Gallagher, W. and Pandit, A. (2010) The Influence of Size and Charge of Chitosan/Polyglutamic Acid Hollow Spheres on Cellular Internalization, Viability and Blood Compatibility. Biomaterials, 31, 8188-8197.
http://dx.doi.org/10.1016/j.biomaterials.2010.07.067

[22]   Conner, S.D. and Schmid, S.L. (2003) Regulated Portals of Entry into the Cell. Nature, 422, 37-44.
http://dx.doi.org/10.1038/nature01451

[23]   Zhao, F., Zhao, Y., Liu, Y., Chang, X., Chen, C. and Zhao, Y. (2011) Cellular Uptake, Intracellular Trafficking, and Cytotoxicity of Nanomaterials. Small, 7, 1322-1337.
http://dx.doi.org/10.1002/smll.201100001

[24]   Bhattacharjee, S., Ershov, D., Fytianos, K., van der Gucht, J., Alink, G.M., Rietjens, I.M., et al. (2012) Cytotoxicity and Cellular Uptake of Tri-Block Copolymer Nanoparticles with Different Size and Surface Characteristics. Particle and Fibre Toxicology, 9, 11.
http://dx.doi.org/10.1186/1743-8977-9-11

[25]   Lai, S.K., Hida, K., Man, S.T., Chen, C., Machamer, C., Schroer, T.A., et al. (2007) Privileged Delivery of Polymer Nanoparticles to the Perinuclear Region of Live Cells via a Non-Clathrin, Non-Degradative Pathway. Biomaterials, 28, 2876-2884.
http://dx.doi.org/10.1016/j.biomaterials.2007.02.021

[26]   Dausend, J., Musyanovych, A., Dass, M., Walther, P., Schrezenmeier, H., Landfester, K., et al. (2008) Uptake Mechanism of Oppositely Charged Fluorescent Nanoparticles in HeLa Cells. Macromolecular Bioscience, 8, 1135-1143.
http://dx.doi.org/10.1002/mabi.200800123

[27]   Win, K.Y. and Feng, S.S. (2005) Effects of Particle Size and Surface Coating on Cellular Uptake of Polymeric Nanoparticles for Oral Delivery of Anticancer Drugs. Biomaterials, 26, 2713-2722.
http://dx.doi.org/10.1016/j.biomaterials.2004.07.050

[28]   Foged, C., Brodin, B., Frokjaer, S. and Sundblad, A. (2005) Particle Size and Surface Charge Affect Particle Uptake by Human Dendritic Cells in an in Vitro Model. International Journal of Pharmaceutics, 298, 315-322.
http://dx.doi.org/10.1016/j.ijpharm.2005.03.035

[29]   Mayer, A., Vadon, M., Rinner, B., Novak, A., Wintersteiger, R. and Frohlich, E. (2009) The Role of Nanoparticle Size in Hemocompatibility. Toxicology, 258, 139-147.
http://dx.doi.org/10.1016/j.tox.2009.01.015

[30]   Mura, S., Hillaireau, H., Nicolas, J., Le Droumaguet, B., Gueutin, C., Zanna, S., et al. (2011) Influence of Surface Charge on the Potential Toxicity of PLGA Nanoparticles towards Calu-3 Cells. International Journal of Nanomedicine, 6, 2591-2605.

[31]   Shen, B.Q., Finkbeiner, W.E., Wine, J.J., Mrsny, R.J. and Widdicombe, J.H. (1994) Calu-3: A Human Airway Epithelial Cell Line That Shows cAMP-Dependent Cl-Secretion. American Journal of Physiology, 266, L493-L501.

[32]   da Paula, A.C., Ramalho, A.S., Farinha, C.M., Cheung, J., Maurisse, R., Gruenert, D.C., et al. (2005) Characterization of Novel Airway Submucosal Gland Cell Models for Cystic Fibrosis Studies. Cellular Physiology and Biochemistry, 15, 251-262.
http://dx.doi.org/10.1159/000087235

[33]   Arap, W., Haedicke, W., Bernasconi, M., Kain, R., Rajotte, D., Krajewski, S., et al. (2002) Targeting the Prostate for Destruction through a Vascular Address. Proceedings of the National Academy of Sciences of the United States of America, 99, 1527-1531.
http://dx.doi.org/10.1073/pnas.241655998

[34]   Gratton, S.E., Ropp, P.A., Pohlhaus, P.D., Luft, J.C., Madden, V.J., Napier, M.E., et al. (2008) The Effect of Particle Design on Cellular Internalization Pathways. Proceedings of the National Academy of Sciences of the United States of America, 105, 11613-11618.
http://dx.doi.org/10.1073/pnas.0801763105

[35]   Schadlich, A., Caysa, H., Mueller, T., Tenambergen, F., Rose, C., Gopferich, A., et al. (2011) Tumor Accumulation of NIR Fluorescent PEG-PLA Nanoparticles: Impact of Particle Size and Human Xenograft Tumor Model. ACS Nano, 5, 8710-8720.
http://dx.doi.org/10.1021/nn2026353

[36]   Kulkarni, S.A. and Feng, S.S. (2013) Effects of Particle Size and Surface Modification on Cellular Uptake and Biodistribution of Polymeric Nanoparticles for Drug Delivery. Pharmaceutical Research, 30, 2512-2522.
http://dx.doi.org/10.1007/s11095-012-0958-3

[37]   Hillery, A.M. and Florence, F.A. (1996) The Effect of Adsorbed Poloxamer 188 and 407 Surfactants on the Intestinal Uptake of 60-nm Polystyrene Particles after Oral Administration in the Rat. International Journal of Pharmaceutics, 132, 123-130.
http://dx.doi.org/10.1016/0378-5173(95)04353-5

[38]   Faraji, A.H. and Wipf, P. (2009) Nanoparticles in Cellular Drug Delivery. Bioorganic & Medicinal Chemistry, 17, 2950-2962.
http://dx.doi.org/10.1016/j.bmc.2009.02.043

[39]   Alexis, F., Pridgen, E., Molnar, L.K. and Farokhzad, O.C. (2008) Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles. Molecular Pharmaceutics, 5, 505-515.
http://dx.doi.org/10.1021/mp800051m

[40]   Nigavekar, S.S., Sung, L.Y., Llanes, M., El-Jawahri, A., Lawrence, T.S., Becker, C.W., et al. (2004) 3H Dendrimer Nanoparticle Organ/Tumor Distribution. Pharmaceutical Research, 21, 476-483.
http://dx.doi.org/10.1023/B:PHAM.0000019302.26097.cc

[41]   Liu, D., Mori, A. and Huang, L. (1992) Role of Liposome Size and RES Blockade in Controlling Biodistribution and Tumor Uptake of GM1-Containing Liposomes. Biochimica et Biophysica Acta, 1104, 95-101.
http://dx.doi.org/10.1016/0005-2736(92)90136-A

[42]   Akiyama, Y., Mori, T., Katayama, Y. and Niidome, T. (2009) The Effects of PEG Grafting Level and Injection Dose on Gold Nanorod Biodistribution in the Tumor-Bearing Mice. Journal of Controlled Release, 139, 81-84.
http://dx.doi.org/10.1016/j.jconrel.2009.06.006

[43]   Ishiwata, H., Suzuki, N., Ando, S., Kikuchi, H. and Kitagawa, T. (2000) Characteristics and Biodistribution of Cationic Liposomes and Their DNA Complexes. Journal of Controlled Release, 69, 139-148.
http://dx.doi.org/10.1016/S0168-3659(00)00293-5

[44]   Vonarbourg, A., Passirani, C., Saulnier, P., Simard, P., Leroux, J.C. and Benoit, J.P. (2006) Evaluation of Pegylated Lipid Nanocapsules versus Complement System Activation and Macrophage Uptake. Journal of Biomedical Materials Research Part A, 78, 620-628.
http://dx.doi.org/10.1002/jbm.a.30711

[45]   Petros, R.A. and DeSimone, J.M. (2010) Strategies in the Design of Nanoparticles for Therapeutic Applications. Nature Reviews Drug Discovery, 9, 615-627.
http://dx.doi.org/10.1038/nrd2591

[46]   Choi, H.S., Liu, W., Misra, P., Tanaka, E., Zimmer, J.P., Itty Ipe, B., et al. (2007) Renal Clearance of Quantum Dots. Nature Biotechnology, 25, 1165-1170.
http://dx.doi.org/10.1038/nbt1340

[47]   Li, S.D. and Huang, L. (2008) Pharmacokinetics and Biodistribution of Nanoparticles. Molecular Pharmaceutics, 5, 496-504.
http://dx.doi.org/10.1021/mp800049w

[48]   Levchenko, T.S., Rammohan, R., Lukyanov, A.N., Whiteman, K.R. and Torchilin, V.P. (2002) Liposome Clearance in Mice: The Effect of a Separate and Combined Presence of Surface Charge and Polymer Coating. International Journal of Pharmaceutics, 240, 95-102.
http://dx.doi.org/10.1016/S0378-5173(02)00129-1

[49]   Yamamoto, Y., Nagasaki, Y., Kato, Y., Sugiyama, Y. and Kataoka, K. (2001) Long-Circulating Poly(Ethylene Glycol)-Poly(D,L-Lactide) Block Copolymer Micelles with Modulated Surface Charge. Journal of Controlled Release, 77, 27-38.
http://dx.doi.org/10.1016/S0168-3659(01)00451-5

[50]   Ma, Z. and Lim, L.Y. (2003) Uptake of Chitosan and Associated Insulin in Caco-2 Cell Monolayers: A Comparison between Chitosan Molecules and Chitosan Nanoparticles. Pharmaceutical Research, 20, 1812-1819.
http://dx.doi.org/10.1023/B:PHAM.0000003379.76417.3e

[51]   Huang, M., Ma, Z., Khor, E. and Lim, L.Y. (2002) Uptake of FITC-Chitosan Nanoparticles by A549 Cells. Pharmaceutical Research, 19, 1488-1494.
http://dx.doi.org/10.1023/A:1020404615898

[52]   Kim, T.H., Park, I.K., Nah, J.W., Choi, Y.J. and Cho, C.S. (2004) Galactosylated Chitosan/DNA Nanoparticles Prepared Using Water-Soluble Chitosan as a Gene Carrier. Biomaterials, 25, 3783-3792.
http://dx.doi.org/10.1016/j.biomaterials.2003.10.063

[53]   Han, H.D., Mangala, L.S., Lee, J.W., Shahzad, M.M., Kim, H.S., Shen, D., et al. (2010) Targeted Gene Silencing Using RGD-Labeled Chitosan Nanoparticles. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 16, 3910-3922.

[54]   Aktas, Y., Yemisci, M., Andrieux, K., Gursoy, R.N., Alonso, M.J., Fernandez-Megia, E., et al. (2005) Development and Brain Delivery of Chitosan-PEG Nanoparticles Functionalized with the Monoclonal Antibody OX26. Bioconjugate Chemistry, 16, 1503-1511.
http://dx.doi.org/10.1021/bc050217o

[55]   Balthasar, S., Michaelis, K., Dinauer, N., von Briesen, H., Kreuter, J. and Langer, K. (2005) Preparation and Characterisation of Antibody Modified Gelatin Nanoparticles as Drug Carrier System for Uptake in Lymphocytes. Biomaterials, 26, 2723-2732.
http://dx.doi.org/10.1016/j.biomaterials.2004.07.047

[56]   Wang, X., Li, J., Wang, Y., Cho, K.J., Kim, G., Gjyrezi, A., et al. (2009) HFT-T, a Targeting Nanoparticle, Enhances Specific Delivery of Paclitaxel to Folate Receptor-Positive Tumors. ACS Nano, 3, 3165-3174.
http://dx.doi.org/10.1021/nn900649v

[57]   Choi, K.Y., Chung, H., Min, K.H., Yoon, H.Y., Kim, K., Park, J.H., et al. (2010) Self-Assembled Hyaluronic Acid Nanoparticles for Active Tumor Targeting. Biomaterials, 31, 106-114.
http://dx.doi.org/10.1016/j.biomaterials.2009.09.030

[58]   Cho, H.J., Yoon, H.Y., Koo, H., Ko, S.H., Shim, J.S., Lee, J.H., et al. (2011) Self-Assembled Nanoparticles Based on Hyaluronic Acid-Ceramide (HA-CE) and Pluronic(R) for Tumor-Targeted Delivery of Docetaxel. Biomaterials, 32, 7181-7190.
http://dx.doi.org/10.1016/j.biomaterials.2011.06.028

[59]   Nam, H.Y., Kwon, S.M., Chung, H., Lee, S.Y., Kwon, S.H., Jeon, H., et al. (2009) Cellular Uptake Mechanism and Intracellular Fate of Hydrophobically Modified Glycol Chitosan Nanoparticles. Journal of Controlled Release, 135, 259-267.

[60]   Chung, T.H., Wu, S.H., Yao, M., Lu, C.W., Lin, Y.S., Hung, Y., et al. (2007) The Effect of Surface Charge on the Uptake and Biological Function of Mesoporous Silica Nanoparticles in 3T3-L1 Cells and Human Mesenchymal Stem Cells. Biomaterials, 28, 2959-2966.
http://dx.doi.org/10.1016/j.biomaterials.2007.03.006

[61]   Ko, J., Park, K., Kim, Y.S., Kim, M.S., Han, J.K., Kim, K., et al. (2007) Tumoral Acidic Extracellular pH Targeting of pH-Responsive MPEG-Poly(Beta-Amino Ester) Block Copolymer Micelles for Cancer Therapy. Journal of Controlled Release, 123, 109-115.

[62]   Park, J.S., Han, T.H., Lee, K.Y., Han, S.S., Hwang, J.J., Moon, D.H., et al. (2006) N-Acetyl Histidine-Conjugated Glycol Chitosan Self-Assembled Nanoparticles for Intracytoplasmic Delivery of Drugs: Endocytosis, Exocytosis and Drug Release. Journal of Controlled Release, 115, 37-45.

[63]   Wang, Y., Gao, S., Ye, W.H., Yoon, H.S. and Yang, Y.Y. (2006) Co-Delivery of Drugs and DNA from Cationic Core-Shell Nanoparticles Self-Assembled from a Biodegradable Copolymer. Nature Materials, 5, 791-796.
http://dx.doi.org/10.1038/nmat1737

[64]   Chawla, J.S. and Amiji, M.M. (2002) Biodegradable Poly(Epsilon-Caprolactone) Nanoparticles for Tumor-Targeted Delivery of taMoxifen. International Journal of Pharmaceutics, 249, 127-138.
http://dx.doi.org/10.1016/S0378-5173(02)00483-0

[65]   Chawla, J.S. and Amiji, M.M. (2003) Cellular Uptake and Concentrations of Tamoxifen upon Administration in Poly(Epsilon-Caprolactone) Nanoparticles. AAPS PharmSci, 5, 28-34.
http://dx.doi.org/10.1208/ps050103

[66]   Cade, D., Ramus, E., Rinaudo, M., Auzely-Velty, R., Delair, T. and Hamaide, T. (2004) Tailoring of Bioresorbable Polymers for Elaboration of Sugar-Functionalized Nanoparticles. Biomacromolecules, 5, 922-927.
http://dx.doi.org/10.1021/bm034504b

[67]   Wang, J., Tian, S., Petros, R.A., Napier, M.E. and Desimone, J.M. (2010) The Complex Role of Multivalency in Nanoparticles Targeting the Transferrin Receptor for Cancer Therapies. Journal of the American Chemical Society, 132, 11306-11313.
http://dx.doi.org/10.1021/ja1043177

[68]   Lee, H., Fonge, H., Hoang, B., Reilly, R.M. and Allen, C. (2010) The Effects of Particle Size and Molecular Targeting on the Intratumoral and Subcellular Distribution of Polymeric Nanoparticles. Molecular Pharmaceutics, 7, 1195-1208.
http://dx.doi.org/10.1021/mp100038h

[69]   Xin, H., Jiang, X., Gu, J., Sha, X., Chen, L., Law, K., et al. (2011) Angiopep-Conjugated Poly(Ethylene Glycol)-co-Poly(Epsilon-Caprolactone) Nanoparticles as Dual-Targeting Drug Delivery System for Brain Glioma. Biomaterials, 32, 4293-4305.
http://dx.doi.org/10.1016/j.biomaterials.2011.02.044

[70]   Kim, H.R., Gil, S., Andrieux, K., Nicolas, V., Appel, M., Chacun, H., et al. (2007) Low-Density Lipoprotein Receptor-Mediated Endocytosis of PEGylated Nanoparticles in Rat Brain Endothelial Cells. Cellular and Molecular Life Sciences: CMLS, 64, 356-364.
http://dx.doi.org/10.1007/s00018-007-6390-x

[71]   Harush-Frenkel, O., Debotton, N., Benita, S. and Altschuler, Y. (2007) Targeting of Nanoparticles to the Clathrin-Mediated Endocytic Pathway. Biochemical and Biophysical Research Communications, 353, 26-32.
http://dx.doi.org/10.1016/j.bbrc.2006.11.135

[72]   Lu, W., Tan, Y.Z., Hu, K.L. and Jiang, X.G. (2005) Cationic Albumin Conjugated Pegylated Nanoparticle with Its Transcytosis Ability and Little Toxicity Against Blood-Brain Barrier. International Journal of Pharmaceutics, 295, 247-260.
http://dx.doi.org/10.1016/j.ijpharm.2005.01.043

[73]   Harush-Frenkel, O., Rozentur, E., Benita, S. and Altschuler, Y. (2008) Surface Charge of Nanoparticles Determines Their Endocytic and Transcytotic Pathway in Polarized MDCK Cells. Biomacromolecules, 9, 435-443.
http://dx.doi.org/10.1021/bm700535p

[74]   Aryal, S., Hu, C.M. and Zhang, L. (2010) Polymer-Cisplatin Conjugate Nanoparticles for Acid-Responsive Drug Delivery. ACS Nano, 4, 251-258.
http://dx.doi.org/10.1021/nn9014032

[75]   Danhier, F., Lecouturier, N., Vroman, B., Jerome, C., Marchand-Brynaert, J., Feron, O., et al. (2009) Paclitaxel-Loaded PEGylated PLGA-Based Nanoparticles: In Vitro and In Vivo Evaluation. Journal of Controlled Release, 133, 11-17.

[76]   Mao, S., Germershaus, O., Fischer, D., Linn, T., Schnepf, R. and Kissel, T. (2005) Uptake and Transport of PEG- Graft-Trimethyl-Chitosan Copolymer-Insulin Nanocomplexes by Epithelial Cells. Pharmaceutical Research, 22, 2058- 2068.
http://dx.doi.org/10.1007/s11095-005-8175-y

[77]   Nukolova, N.V., Oberoi, H.S., Cohen, S.M., Kabanov, A.V. and Bronich, T.K. (2011) Folate-Decorated Nanogels for Targeted Therapy of Ovarian Cancer. Biomaterials, 32, 5417-5426.
http://dx.doi.org/10.1016/j.biomaterials.2011.04.006

[78]   Cho, C.S., Cho, K.Y., Park, I.K., Kim, S.H., Sasagawa, T., Uchiyama, M., et al. (2001) Receptor-Mediated Delivery of All Trans-Retinoic Acid to Hepatocyte Using Poly(L-Lactic Acid) Nanoparticles Coated with Galactose-Carrying Polystyrene. Journal of Controlled Release, 77, 7-15.

[79]   Banquy, X., Leclair, G., Rabanel, J.M., Argaw, A., Bouchard, J.F., Hildgen, P., et al. (2008) Selectins Ligand Decorated Drug Carriers for Activated Endothelial Cell Targeting. Bioconjugate Chemistry, 19, 2030-2039.
http://dx.doi.org/10.1021/bc800257m

[80]   Nasongkla, N., Bey, E., Ren, J., Ai, H., Khemtong, C., Guthi, J.S., et al. (2006) Multifunctional Polymeric Micelles as Cancer-Targeted, MRI-Ultrasensitive Drug Delivery Systems. Nano Letters, 6, 2427-2430.
http://dx.doi.org/10.1021/nl061412u

[81]   Prabha, S. and Labhasetwar, V. (2004) Critical Determinants in PLGA/PLA Nanoparticle-Mediated Gene Expression. Pharmaceutical Research, 21, 354-364.
http://dx.doi.org/10.1023/B:PHAM.0000016250.56402.99

[82]   Musumeci, T., Ventura, C.A., Giannone, I., Ruozi, B., Montenegro, L., Pignatello, R., et al. (2006) PLA/PLGA Nanoparticles for Sustained Release of Docetaxel. International Journal of Pharmaceutics, 325, 172-179.
http://dx.doi.org/10.1016/j.ijpharm.2006.06.023

[83]   Prabha, S., Zhou, W.Z., Panyam, J. and Labhasetwar, V. (2002) Size-Dependency of Nanoparticle-Mediated Gene Transfection: Studies with Fractionated Nanoparticles. International Journal of Pharmaceutics, 244, 105-115.
http://dx.doi.org/10.1016/S0378-5173(02)00315-0

[84]   Sahoo, S.K., Panyam, J., Prabha, S. and Labhasetwar, V. (2002) Residual Polyvinyl Alcohol Associated with Poly (D,L-Lactide-co-Glycolide) Nanoparticles Affects Their Physical Properties and Cellular Uptake. Journal of Controlled Release, 82, 105-114.

[85]   Sahoo, S.K. and Labhasetwar, V. (2005) Enhanced Antiproliferative Activity of Transferrin-Conjugated Paclitaxel-Loaded Nanoparticles Is Mediated via Sustained Intracellular Drug Retention. Molecular Pharmaceutics, 2, 373-383.
http://dx.doi.org/10.1021/mp050032z

[86]   Obermajer, N., Kocbek, P., Repnik, U., Kuznik, A., Cegnar, M., Kristl, J., et al. (2007) Immunonanoparticles—An Effective Tool to Impair Harmful Proteolysis in Invasive Breast Tumor Cells. The FEBS Journal, 274, 4416-4427.
http://dx.doi.org/10.1111/j.1742-4658.2007.05971.x

[87]   Davda, J. and Labhasetwar, V. (2002) Characterization of Nanoparticle Uptake by Endothelial Cells. International Journal of Pharmaceutics, 233, 51-59.
http://dx.doi.org/10.1016/S0378-5173(01)00923-1

[88]   Mo, Y. and Lim, L.Y. (2005) Preparation and in Vitro Anticancer Activity of Wheat Germ Agglutinin (WGA)-Conjugated PLGA Nanoparticles Loaded with Paclitaxel and Isopropyl Myristate. Journal of Controlled Release, 107, 30-42.

[89]   Mo, Y. and Lim, L.Y. (2005) Paclitaxel-Loaded PLGA Nanoparticles: Potentiation of Anticancer Activity by Surface Conjugation with Wheat Germ Agglutinin. Journal of Controlled Release, 108, 244-262.

[90]   Mo, Y. and Lim, L.Y. (2004) Mechanistic Study of the Uptake of Wheat Germ Agglutinin-Conjugated PLGA Nanoparticles by A549 Cells. Journal of Pharmaceutical Sciences, 93, 20-28.
http://dx.doi.org/10.1002/jps.10507

[91]   McCarron, P.A., Marouf, W.M., Quinn, D.J., Fay, F., Burden, R.E., Olwill, S.A., et al. (2008) Antibody Targeting of Camptothecin-Loaded PLGA Nanoparticles to Tumor Cells. Bioconjugate Chemistry, 19, 1561-1569.
http://dx.doi.org/10.1021/bc800057g

[92]   Tosi, G., Fano, R.A., Bondioli, L., Badiali, L., Benassi, R., Rivasi, F., et al. (2011) Investigation on Mechanisms of Glycopeptide Nanoparticles for Drug Delivery across the Blood-Brain Barrier. Nanomedicine, 6, 423-436.
http://dx.doi.org/10.2217/nnm.11.11

[93]   Fonseca, C., Simoes, S. and Gaspar, R. (2002) Paclitaxel-Loaded PLGA Nanoparticles: Preparation, Physicochemical Characterization and in Vitro Anti-Tumoral Activity. Journal of Controlled Release, 83, 273-286.

[94]   Xie, J. and Wang, C.H. (2005) Self-Assembled Biodegradable Nanoparticles Developed by Direct Dialysis for the Delivery of Paclitaxel. Pharmaceutical Research, 22, 2079-2090.
http://dx.doi.org/10.1007/s11095-005-7782-y

[95]   Esmaeili, F., Dinarvand, R., Ghahremani, M.H., Ostad, S.N., Esmaily, H. and Atyabi, F. (2010) Cellular Cytotoxicity and In-Vivo Biodistribution of Docetaxel Poly(Lactide-co-Glycolide) Nanoparticles. Anti-Cancer Drugs, 21, 43-52.
http://dx.doi.org/10.1097/CAD.0b013e328331f934

[96]   Betancourt, T., Brown, B. and Brannon-Peppas, L. (2007) Doxorubicin-Loaded PLGA Nanoparticles by Nanoprecipitation: Preparation, Characterization and in Vitro Evaluation. Nanomedicine, 2, 219-232.
http://dx.doi.org/10.2217/17435889.2.2.219

[97]   Manchanda, R., Fernandez-Fernandez, A., Nagesetti, A. and McGoron, A.J. (2010) Preparation and Characterization of a Polymeric (PLGA) Nanoparticulate Drug Delivery System with Simultaneous Incorporation of Chemotherapeutic and Thermo-Optical Agents. Colloids and Surfaces B: Biointerfaces, 75, 260-267.
http://dx.doi.org/10.1016/j.colsurfb.2009.08.043

[98]   Yallapu, M.M., Gupta, B.K., Jaggi, M. and Chauhan, S.C. (2010) Fabrication of Curcumin Encapsulated PLGA Nanoparticles for Improved Therapeutic Effects in Metastatic Cancer Cells. Journal of Colloid and Interface Science, 351, 19-29.
http://dx.doi.org/10.1016/j.jcis.2010.05.022

[99]   Yan, F., Zhang, C., Zheng, Y., Mei, L., Tang, L., Song, C., et al. (2010) The Effect of Poloxamer 188 on Nanoparticle Morphology, Size, Cancer Cell Uptake, and Cytotoxicity. Nanomedicine, 6, 170-178.
http://dx.doi.org/10.1016/j.nano.2009.05.004

[100]   Song, X.R., Cai, Z., Zheng, Y., He, G., Cui, F.Y., Gong, D.Q., et al. (2009) Reversion of Multidrug Resistance by Co-Encapsulation of Vincristine and Verapamil in PLGA Nanoparticles. European Journal of Pharmaceutical Sciences: Official Journal of the European Federation for Pharmaceutical Sciences, 37, 300-305.

[101]   Zeisser-Labouebe, M., Lange, N., Gurny, R. and Delie, F. (2006) Hypericin-Loaded Nanoparticles for the Photodynamic Treatment of Ovarian Cancer. International Journal of Pharmaceutics, 326, 174-181.
http://dx.doi.org/10.1016/j.ijpharm.2006.07.012

[102]   Shah, N., Chaudhari, K., Dantuluri, P., Murthy, R.S. and Das, S. (2009) Paclitaxel-Loaded PLGA Nanoparticles Surface Modified with Transferrin and Pluronic((R))P85, an in Vitro Cell Line and in Vivo Biodistribution Studies on Rat Model. Journal of Drug Targeting, 17, 533-542.
http://dx.doi.org/10.1080/10611860903046628

[103]   Win, K.Y. and Feng, S.S. (2006) In Vitro and in Vivo Studies on Vitamin E TPGS-Emulsified Poly(D,L-Lactic-co-Glycolic Acid) Nanoparticles for Paclitaxel Formulation. Biomaterials, 27, 2285-2291.
http://dx.doi.org/10.1016/j.biomaterials.2005.11.008

[104]   Dong, Y. and Feng, S.S. (2007) Poly(D,L-Lactide-co-Glycolide) (PLGA) Nanoparticles Prepared by High Pressure Homogenization for Paclitaxel Chemotherapy. International Journal of Pharmaceutics, 342, 208-214.
http://dx.doi.org/10.1016/j.ijpharm.2007.04.031

[105]   Bondioli, L., Costantino, L., Ballestrazzi, A., Lucchesi, D., Boraschi, D., Pellati, F., et al. (2010) PLGA Nanoparticles Surface Decorated with the Sialic Acid, N-Acetylneuraminic Acid. Biomaterials, 31, 3395-3403.
http://dx.doi.org/10.1016/j.biomaterials.2010.01.049

[106]   Zheng, Y., Yu, B., Weecharangsan, W., Piao, L., Darby, M., Mao, Y., et al. (2010) Transferrin-Conjugated Lipid-Coated PLGA Nanoparticles for Targeted Delivery of Aromatase Inhibitor 7alpha-APTADD to Breast Cancer Cells. International Journal of Pharmaceutics, 390, 234-241.
http://dx.doi.org/10.1016/j.ijpharm.2010.02.008

[107]   Kou, G., Gao, J., Wang, H., Chen, H., Li, B., Zhang, D., et al. (2007) Preparation and Characterization of Paclitaxel-Loaded PLGA Nanoparticles Coated with Cationic SM5-1 Single-Chain Antibody. Journal of Biochemistry and Molecular Biology, 40, 731-739.
http://dx.doi.org/10.5483/BMBRep.2007.40.5.731

[108]   Kocbek, P., Obermajer, N., Cegnar, M., Kos, J. and Kristl, J. (2007) Targeting Cancer Cells Using PLGA Nanoparticles Surface Modified with Monoclonal Antibody. Journal of Controlled Release, 120, 18-26.

[109]   Acharya, S., Dilnawaz, F. and Sahoo, S.K. (2009) Targeted Epidermal Growth Factor Receptor Nanoparticle Bioconjugates for Breast Cancer Therapy. Biomaterials, 30, 5737-5750.
http://dx.doi.org/10.1016/j.biomaterials.2009.07.008

[110]   Sun, B., Ranganathan, B. and Feng, S.S. (2008) Multifunctional Poly(D,L-Lactide-co-Glycolide)/Montmorillonite (PLGA/MMT) Nanoparticles Decorated by Trastuzumab for Targeted Chemotherapy of Breast Cancer. Biomaterials, 29, 475-486.
http://dx.doi.org/10.1016/j.biomaterials.2007.09.038

[111]   Gao, J., Kou, G., Wang, H., Chen, H., Li, B., Lu, Y., et al. (2009) PE38KDEL-Loaded Anti-HER2 Nanoparticles Inhibit Breast Tumor Progression with Reduced Toxicity and Immunogenicity. Breast Cancer Research and Treatment, 115, 29-41.
http://dx.doi.org/10.1007/s10549-008-0043-0

[112]   Bicho, A., Peca, I.N., Roque, A.C. and Cardoso, M.M. (2010) Anti-CD8 Conjugated Nanoparticles to Target Mammalian Cells Expressing CD8. International Journal of Pharmaceutics, 399, 80-86.
http://dx.doi.org/10.1016/j.ijpharm.2010.08.005

[113]   Cruz, L.J., Tacken, P.J., Fokkink, R., Joosten, B., Stuart, M.C., Albericio, F., et al. (2010) Targeted PLGA Nano- but Not Microparticles Specifically Deliver Antigen to Human Dendritic Cells via DC-SIGN in Vitro. Journal of Controlled Release, 144, 118-126.

[114]   Alshamsan, A., Haddadi, A., Hamdy, S., Samuel, J., El-Kadi, A.O., Uludag, H., et al. (2010) STAT3 Silencing in Dendritic Cells by siRNA Polyplexes Encapsulated in PLGA Nanoparticles for the Modulation of Anticancer Immune Response. Molecular Pharmaceutics, 7, 1643-1654.
http://dx.doi.org/10.1021/mp100067u

[115]   Ghotbi, Z., Haddadi, A., Hamdy, S., Hung, R.W., Samuel, J. and Lavasanifar, A. (2011) Active Targeting of Dendritic Cells with Mannan-Decorated PLGA Nanoparticles. Journal of Drug Targeting, 19, 281-292.
http://dx.doi.org/10.3109/1061186X.2010.499463

[116]   Haddadi, A., Elamanchili, P., Lavasanifar, A., Das, S., Shapiro, J. and Samuel, J. (2008) Delivery of Rapamycin by PLGA Nanoparticles Enhances Its Suppressive Activity on Dendritic Cells. Journal of Biomedical Materials Research Part A, 84, 885-898.
http://dx.doi.org/10.1002/jbm.a.31373

[117]   Panyam, J., Williams, D., Dash, A., Leslie-Pelecky, D. and Labhasetwar, V. (2004) Solid-State Solubility Influences Encapsulation and Release of Hydrophobic Drugs from PLGA/PLA Nanoparticles. Journal of Pharmaceutical Sciences, 93, 1804-1814.
http://dx.doi.org/10.1002/jps.20094

[118]   Panyam, J. and Labhasetwar, V. (2003) Dynamics of Endocytosis and Exocytosis of Poly(D,L-Lactide-co-Glycolide) Nanoparticles in Vascular Smooth Muscle Cells. Pharmaceutical Research, 20, 212-20.
http://dx.doi.org/10.1023/A:1022219003551

[119]   Panyam, J., Zhou, W.Z., Prabha, S., Sahoo, S.K. and Labhasetwar, V. (2002) Rapid Endo-Lysosomal Escape of Poly- (DL-Lactide-co-Glycolide) Nanoparticles: Implications for Drug and Gene Delivery. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 16, 1217-1226.

[120]   Vasir, J.K. and Labhasetwar, V. (2007)Biodegradable nanoparticles for cytosolic delivery of therapeutics. Advanced drug delivery reviews, 5, 718-728.
http://dx.doi.org/10.1016/j.addr.2007.06.003

[121]   Zhang, N., Chittasupho, C., Duangrat, C., Siahaan, T.J. and Berkland, C. (2008) PLGA Nanoparticle-Peptide Conjugate Effectively Targets Intercellular Cell-Adhesion Molecule-1. Bioconjugate Chemistry, 19, 145-152.
http://dx.doi.org/10.1021/bc700227z

[122]   Townsend, S.A., Evrony, G.D., Gu, F.X., Schulz, M.P., Brown Jr., R.H. and Langer, R. (2007) Tetanus Toxin C Fragment-Conjugated Nanoparticles for Targeted Drug Delivery to Neurons. Biomaterials, 28, 5176-51784.
http://dx.doi.org/10.1016/j.biomaterials.2007.08.011

[123]   Cheng, J., Teply, B.A., Sherifi, I., Sung, J., Luther, G., Gu, F.X., et al. (2007) Formulation of Functionalized PLGA-PEG Nanoparticles for in Vivo Targeted Drug Delivery. Biomaterials, 28, 869-876.
http://dx.doi.org/10.1016/j.biomaterials.2006.09.047

[124]   Dhar, S., Gu, F.X., Langer, R., Farokhzad, O.C. and Lippard, S.J. (2008) Targeted Delivery of Cisplatin to Prostate Cancer Cells by Aptamer Functionalized Pt(IV) Prodrug-PLGA-PEG Nanoparticles. Proceedings of the National Academy of Sciences of the United States of America, 105, 17356-17361.
http://dx.doi.org/10.1073/pnas.0809154105

[125]   Li, J., Feng, L., Fan, L., Zha, Y., Guo, L., Zhang, Q., et al. (2011) Targeting the Brain with PEG-PLGA Nanoparticles Modified with Phage-Displayed Peptides. Biomaterials, 32, 4943-4950.
http://dx.doi.org/10.1016/j.biomaterials.2011.03.031

[126]   Gryparis, E.C., Hatziapostolou, M., Papadimitriou, E. and Avgoustakis, K. (2007) Anticancer Activity of Cisplatin-Loaded PLGA-mPEG Nanoparticles on LNCaP Prostate Cancer Cells. European Journal of Pharmaceutics and Biopharmaceutics: Official Journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV, 67, 1-8.

[127]   Wang, Z., Chui, W.K. and Ho, P.C. (2009) Design of a Multifunctional PLGA Nanoparticulate Drug Delivery System: Evaluation of Its Physicochemical Properties and Anticancer Activity to Malignant Cancer Cells. Pharmaceutical Research, 26, 1162-1171.
http://dx.doi.org/10.1007/s11095-009-9837-y

[128]   Danhier, F., Vroman, B., Lecouturier, N., Crokart, N., Pourcelle, V., Freichels, H., et al. (2009) Targeting of Tumor Endothelium by RGD-Grafted PLGA-Nanoparticles Loaded with Paclitaxel. Journal of Controlled Release, 140, 166-173.

[129]   Patil, Y., Sadhukha, T., Ma, L. and Panyam, J. (2009) Nanoparticle-Mediated Simultaneous and Targeted Delivery of Paclitaxel and Tariquidar Overcomes Tumor Drug Resistance. Journal of Controlled Release, 136, 21-29.

[130]   Farokhzad, O.C., Cheng, J., Teply, B.A., Sherifi, I., Jon, S., Kantoff, P.W., et al. (2006) Targeted Nanoparticle-Ap-tamer Bioconjugates for Cancer Chemotherapy in Vivo. Proceedings of the National Academy of Sciences of the United States of America, 103, 6315-6320.
http://dx.doi.org/10.1073/pnas.0601755103

[131]   Esmaeili, F., Ghahremani, M.H., Ostad, S.N., Atyabi, F., Seyedabadi, M., Malekshahi, M.R., et al. (2008) Folate-Receptor-Targeted Delivery of Docetaxel Nanoparticles Prepared by PLGA-PEG-Folate Conjugate. Journal of Drug Targeting, 16, 415-423.
http://dx.doi.org/10.1080/10611860802088630

[132]   Gu, F., Zhang, L., Teply, B.A., Mann, N., Wang, A., Radovic-Moreno, A.F., et al. (2008) Precise Engineering of Targeted Nanoparticles by Using Self-Assembled Biointegrated Block Copolymers. Proceedings of the National Academy of Sciences of the United States of America, 105, 2586-2591.
http://dx.doi.org/10.1073/pnas.0711714105

[133]   Bivas-Benita, M., Romeijn, S., Junginger, H.E. and Borchard, G. (2004) PLGA-PEI Nanoparticles for Gene Delivery to Pulmonary Epithelium. European Journal of Pharmaceutics and Biopharmaceutics: Official Journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV, 58, 1-6.

[134]   Patil, Y.B., Swaminathan, S.K., Sadhukha, T., Ma, L. and Panyam, J. (2010) The Use of Nanoparticle-Mediated Targeted Gene Silencing and Drug Delivery to Overcome Tumor Drug Resistance. Biomaterials, 31, 358-65.
http://dx.doi.org/10.1016/j.biomaterials.2009.09.048

[135]   Chen, H., Zheng, Y., Tian, G., Tian, Y., Zeng, X., Liu, G., et al. (2011) Oral Delivery of DMAB-Modified Docetaxel-Loaded PLGA-TPGS Nanoparticles for Cancer Chemotherapy. Nanoscale Research Letters, 6, 4.

[136]   Zhang, Z.P., Lee, S.H. and Feng, S.-S. (2007) Folate-Decorated Poly(Lactide-co-Glycolide)-Vitamin E TPGS Nano-particles for Targeted Drug Delivery. Biomaterials, 28, 1889-1899.
http://dx.doi.org/10.1016/j.biomaterials.2006.12.018

[137]   Ma, Y., Zheng, Y., Liu, K., Tian, G., Tian, Y., Xu, L., et al. (2010) Nanoparticles of Poly(Lactide-Co-Glycolide)-d-a-Tocopheryl Polyethylene Glycol 1000 Succinate Random Copolymer for Cancer Treatment. Nanoscale Research Letters, 5, 1161-1169.
http://dx.doi.org/10.1007/s11671-010-9620-3

[138]   Iwasaki, Y., Maie, H. and Akiyoshi, K. (2007) Cell-Specific Delivery of Polymeric Nanoparticles to Carbohydrate-Tagging Cells. Biomacromolecules, 8, 3162-3168.
http://dx.doi.org/10.1021/bm700606z

[139]   Shenoy, D., Little, S., Langer, R. and Amiji, M. (2005) Poly(Ethylene Oxide)-Modified Poly(Beta-Amino Ester) Nanoparticles as a pH-Sensitive System for Tumor-Targeted Delivery of Hydrophobic Drugs: Part 2. In Vivo Distribution and Tumor Localization Studies. Pharmaceutical Research, 22, 2107-2114.
http://dx.doi.org/10.1007/s11095-005-8343-0

[140]   Green, J.J., Chiu, E., Leshchiner, E.S., Shi, J., Langer, R. and Anderson, D.G. (2007) Electrostatic Ligand Coatings of Nanoparticles Enable Ligand-Specific Gene Delivery to Human Primary Cells. Nano Letters, 7, 874-879.
http://dx.doi.org/10.1021/nl062395b

[141]   Ding, H., Inoue, S., Ljubimov, A.V., Patil, R., Portilla-Arias, J., Hu, J., et al. (2010) Inhibition of Brain Tumor Growth by Intravenous Poly(β-L-Malic Acid) Nanobioconjugate with pH-Dependent Drug Release. Proceedings of the National Academy of Sciences of the United States of America, 107, 18143-18148.
http://dx.doi.org/10.1073/pnas.1003919107

[142]   Inoue, S., Ding, H., Portilla-Arias, J., Hu, J., Konda, B., Fujita, M., et al. (2011) Polymalic Provides Efficient Systemic Breast Cancer Treatment by Inhibiting Both HER2/Neu Receptor Synthesis and Activity. Cancer Research, 71, 1454-1464.
http://dx.doi.org/10.1158/0008-5472.CAN-10-3093

[143]   Liang, H.F., Chen, S.C., Chen, M.C., Lee, P.W., Chen, C.T. and Sung, H.W. (2006) Paclitaxel-Loaded Poly(Gamma-Glutamic Acid)-Poly(Lactide) Nanoparticles as a Targeted Drug Delivery System against Cultured HepG2 Cells. Bioconjugate Chemistry, 17, 291-299.
http://dx.doi.org/10.1021/bc0502107

[144]   Lai, S.K., Hida, K., Chen, C. and Hanes, J. (2008) Characterization of the Intracellular Dynamics of a Non-Degradative Pathway Accessed by Polymer Nanoparticles. Journal of Controlled Release, 125, 107-111.

[145]   Bellocq, N.C., Pun, S.H., Jensen, G.S. and Davis, M.E. (2003) Transferrin-Containing, Cyclodextrin Polymer-Based Particles for Tumor-Targeted Gene Delivery. Bioconjugate Chemistry, 14, 1122-1132.
http://dx.doi.org/10.1021/bc034125f

 
 
Top