Nanomedicine & Nanotechnology
`
`Ma and Mumper, J Nanomed Nanotechol 2013, 4:2
`http://dx.doi.org/10.4172/2157-7439.1000164
`
`Review Article
`
`Open Access
`
`Paclitaxel Nano-Delivery Systems: A Comprehensive Review
`Ping Ma1 and Russell J. Mumper1,2*
`1Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill,
`Chapel Hill, NC 27599, USA
`2UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA
`
`Abstract
`Paclitaxel is one of the most effective chemotherapeutic drugs ever developed and is active against a broad
`range of cancers, such as lung, ovarian, and breast cancers. Due to its low water solubility, paclitaxel is formulated
`in a mixture of Cremophor EL and dehydrated ethanol (50:50, v/v) a combination known as Taxol. However, Taxol
`has some severe side effects related to Cremophor EL and ethanol. Therefore, there is an urgent need for the
`development of alternative Taxol formulations. The encapsulation of paclitaxel in biodegradable and non-toxic nano-
`delivery systems can protect the drug from degradation during circulation and in-turn protect the body from toxic side
`effects of the drug thereby lowering its toxicity, increasing its circulation half-life, exhibiting improved pharmacokinetic
`profiles, and demonstrating better patient compliance. Also, nanoparticle-based delivery systems can take advantage
`of the enhanced permeability and retention (EPR) effect for passive tumor targeting, therefore, they are promising
`carriers to improve the therapeutic index and decrease the side effects of paclitaxel. To date, paclitaxel albumin-bound
`nanoparticles (Abraxane®) have been approved by the FDA for the treatment of metastatic breast cancer and non-
`small cell lung cancer (NSCLC). In addition, there are a number of novel paclitaxel nanoparticle formulations in clinical
`trials. In this comprehensive review, several types of developed paclitaxel nano-delivery systems will be covered and
`discussed, such as polymeric nanoparticles, lipid-based formulations, polymer conjugates, inorganic nanoparticles,
`carbon nanotubes, nanocrystals, and cyclodextrin nanoparticles.
`
`Keywords:
`acid);
`Poly(lactic-co-glycolic
`Nanoparticles;
`Nanocapsules; Drug-polymer conjugates; Multi-drug resistance; Solid
`lipid nanoparticles
`Abbreviations: Ab: Antibody; Au NPs: Gold Nanoparticles; AUC:
`Area Under the Curve; BBB: Blood-Brain Barrier; BrC16: 2’-2-Bro-Mo-
`hexadecanoyl; Brij 78: Polyoxyl 20-Stearyl Ether; BSA: Bovine Serum
`Albumin; C22-PX: 2’-Behenoyl-Paclitaxel Conjugate; CD: Cyclodex-
`trin; CHO: Cholesterol; Cmax: Maximum Concentration; CMC: Critical
`Micelle Concentration; CNT: Carbon Nanotubes; DHA: Docosahexae-
`noic Acid; DLPC: 1,2-Dilauroylphosphatidylcholine; DMAB: Dido-
`decyldimethylammonium Bromide; DNA: Deoxyribonucleic Acid;
`DOPC: 1,2-Dioleoyl-Sn-Glycero-3-Phosphocholine; DOTAP: N-[1-
`[2,3-Dioleoyloxy]Propyl]-N,N,N-Trimethyl-Ammonium Methylsul-
`fate; DPPC: Dipalmitoyl-Phosphatidylcholine; DSPC: 1,2-Distearoyl-
`Sn-Glycero-3-Phosphocholine; EE: Entrapment Efficiency; EPC: Egg
`Phosphatidylcholine; EPR: Enhanced Permeability and Retention; FA:
`Fatty Acid; FITC: Fluorescein Isothiocyanate; h: Hour; HA: Hyaluronic
`Acid; HER2: Human Epidermal Growth Factor Receptor 2; HO-GC:
`Hydrotropic Oligomer-Glycol Chitosan; HPG: Hyperbranched Polyg-
`lycerol; HPMA: N-[2-Hydroxypropyl]Methacrylamide; HSA: Human
`Serum Albumin; HSPC: Hydrogenated Soybean Phosphatidylcholine;
`IC50: Half Maximal Inhibitory Concentration; i.p: Intraperitoneal; i.v:
`Intravenous; kg: Kilogram; LRP1: Low-Density Lipoprotein Recep-
`tor-Related Protein 1; mAb: Monoclonal Antibody; MDR: Multiple
`Drug Resistance; mg: Milligram; min: Minute; mL: Milliliter; MMT:
`Montmorillonite; MNP: Magnetic Nanoparticle; mPEG: Methoxy
`Poly[Ethylene Glycol]; MTD: Maximum Tolerated Dose; NC: Nano-
`capsule; NSCLC: Non-Small Cell Lung Cancer; ng: Nanogram; NMR:
`Nuclear Magnetic Resonance; NP: Nanoparticle; OSA: Octyl-Modified
`Bovine Serum Albumin; PACA: Poly[Alkyl Cyanoacrylate]; PAMAM:
`Poly[Amidoamine]; PbAE: Poly[β-Amino Ester]; PBCA: Poly[Butyl
`Cyanoacrylate]; PCL: Poly [ε-Caprolactone]; PE: Phosphatidyl Etha-
`nolamine; PEEP: Poly[Ethyl Ethylene Phosphate]; PEG: Poly[Ethylene
`Glycol]; PEG-DSPE: Polyethylene Glycol-Distearoylphosphatidyletha-
`nolamine; PEI: Polyethylenimine; PEO-b-PCL: Poly[Ethylene Oxide]-
`block-Poly[ε-Caprolactone]; PEO-PbAE: Poly[Ethylene Oxide]-Mod-
`
`ified Poly[β-Amino Ester]; PEO-PPO-PEO: Poly[Ethylene Oxide]-
`Poly[Propylene Oxide]-Poly[Ethylene Oxide]; PEtOz: Poly[2-Ethyl-
`2-Oxazoline]; PG: Poly[L-Glutamic Acid]; PGG: Poly[L-γ-Glutamyl-
`Glutamine]; P-gp: P-glycoprotein; PLA: Poly[L-Lactide]; PLGA:
`Poly[Lactic-Co-Glycolic Acid]; Pluronic P85: Poly[Oxyethylene-b-
`Oxypropylene-b-Oxyethylene]; PPEEA : Poly[2-Aminoethyl Ethylene
`Phosphate]; PVA: Poly[Vinyl Alcohol]; PX: Paclitaxel; Ref: Reference;
`RES: Reticuloendothelial System; RHAMM: Hyaluronan-Mediated
`Motility Receptor; RNA: Ribonucleic Acid; s.c.: Subcutaneous; SD:
`Standard Deviation; SEC: Size Exclusion Chromatography; siRNA:
`Small Interfering RNA; SLN: Solid Lipid Nanoparticle; SPAnNa: Poly
`[Aniline-co-Sodium N-[1-One-Butyric Acid] Aniline]; SSMM: Steri-
`cally Stabilized Mixed Micelle; t1/2: Half-Life; TEM: Transmission Elec-
`tron Microscopy; TPGS: D-α-Tocopheryl Polyethylene Glycol 1000
`Succinate; µg: Microgram; µL: Microliter; VIP : Vasoactive Intestinal
`Peptide; vs: Versus
`Paclitaxel and its Limitations
`Paclitaxel (PX), isolated from the bark of Pacific Yew (Taxus
`brevifolia), which was first discovered by Mrs. Monroe E. Wall and
`Mansukh C. Wani, is a white crystalline powder with the melting point
`
`*Corresponding author: Russell J. Mumper, Vice Dean and John A. McNeill
`Distinguished Professor, Center for Nanotechnology in Drug Delivery, Division
`of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy CB# 7355,
`100G Beard Hall, University of North Carolina at Chapel Hill, Chapel Hill, North
`Carolina 27599-7355, USA, Tel: +1-919-966-1271; Fax: +1-919-966-6919; E-mail:
`mumper@email.unc.edu
`Received January 17, 2013; Accepted February 15, 2013; Published February
`18, 2013
`Citation: Ma P, Mumper RJ (2013) Paclitaxel Nano-Delivery Systems: A
`Comprehensive Review. J Nanomed Nanotechol 4: 164. doi:10.4172/2157-
`7439.1000164
`Copyright: © 2013 Ma P, et al. This is an open-access article distributed under
`the terms of the Creative Commons Attribution License, which permits unrestricted
`use, distribution, and reproduction in any medium, provided the original author and
`source are credited.
`
`J Nanomed Nanotechol
`ISSN:2157-7439 JNMNT, an open access journal
`
`Volume 4 • Issue 2 • 1000164
`
`

`

`Nanomedicine & Nanotechnology
`
`Ma and Mumper, J Nanomed Nanotechol 2013, 4:2
`http://dx.doi.org/10.4172/2157-7439.1000164
`
`Review Article
`
`Open Access
`
`Paclitaxel Nano-Delivery Systems: A Comprehensive Review
`Ping Ma1 and Russell J. Mumper1,2*
`1Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill,
`Chapel Hill, NC 27599, USA
`2UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA
`
`Abstract
`Paclitaxel is one of the most effective chemotherapeutic drugs ever developed and is active against a broad
`range of cancers, such as lung, ovarian, and breast cancers. Due to its low water solubility, paclitaxel is formulated
`in a mixture of Cremophor EL and dehydrated ethanol (50:50, v/v) a combination known as Taxol. However, Taxol
`has some severe side effects related to Cremophor EL and ethanol. Therefore, there is an urgent need for the
`development of alternative Taxol formulations. The encapsulation of paclitaxel in biodegradable and non-toxic nano-
`delivery systems can protect the drug from degradation during circulation and in-turn protect the body from toxic side
`effects of the drug thereby lowering its toxicity, increasing its circulation half-life, exhibiting improved pharmacokinetic
`profiles, and demonstrating better patient compliance. Also, nanoparticle-based delivery systems can take advantage
`of the enhanced permeability and retention (EPR) effect for passive tumor targeting, therefore, they are promising
`carriers to improve the therapeutic index and decrease the side effects of paclitaxel. To date, paclitaxel albumin-bound
`nanoparticles (Abraxane®) have been approved by the FDA for the treatment of metastatic breast cancer and non-
`small cell lung cancer (NSCLC). In addition, there are a number of novel paclitaxel nanoparticle formulations in clinical
`trials. In this comprehensive review, several types of developed paclitaxel nano-delivery systems will be covered and
`discussed, such as polymeric nanoparticles, lipid-based formulations, polymer conjugates, inorganic nanoparticles,
`carbon nanotubes, nanocrystals, and cyclodextrin nanoparticles.
`
`Keywords:
`acid);
`Poly(lactic-co-glycolic
`Nanoparticles;
`Nanocapsules; Drug-polymer conjugates; Multi-drug resistance; Solid
`lipid nanoparticles
`Abbreviations: Ab: Antibody; Au NPs: Gold Nanoparticles; AUC:
`Area Under the Curve; BBB: Blood-Brain Barrier; BrC16: 2’-2-Bro-Mo-
`hexadecanoyl; Brij 78: Polyoxyl 20-Stearyl Ether; BSA: Bovine Serum
`Albumin; C22-PX: 2’-Behenoyl-Paclitaxel Conjugate; CD: Cyclodex-
`trin; CHO: Cholesterol; Cmax: Maximum Concentration; CMC: Critical
`Micelle Concentration; CNT: Carbon Nanotubes; DHA: Docosahexae-
`noic Acid; DLPC: 1,2-Dilauroylphosphatidylcholine; DMAB: Dido-
`decyldimethylammonium Bromide; DNA: Deoxyribonucleic Acid;
`DOPC: 1,2-Dioleoyl-Sn-Glycero-3-Phosphocholine; DOTAP: N-[1-
`[2,3-Dioleoyloxy]Propyl]-N,N,N-Trimethyl-Ammonium Methylsul-
`fate; DPPC: Dipalmitoyl-Phosphatidylcholine; DSPC: 1,2-Distearoyl-
`Sn-Glycero-3-Phosphocholine; EE: Entrapment Efficiency; EPC: Egg
`Phosphatidylcholine; EPR: Enhanced Permeability and Retention; FA:
`Fatty Acid; FITC: Fluorescein Isothiocyanate; h: Hour; HA: Hyaluronic
`Acid; HER2: Human Epidermal Growth Factor Receptor 2; HO-GC:
`Hydrotropic Oligomer-Glycol Chitosan; HPG: Hyperbranched Polyg-
`lycerol; HPMA: N-[2-Hydroxypropyl]Methacrylamide; HSA: Human
`Serum Albumin; HSPC: Hydrogenated Soybean Phosphatidylcholine;
`IC50: Half Maximal Inhibitory Concentration; i.p: Intraperitoneal; i.v:
`Intravenous; kg: Kilogram; LRP1: Low-Density Lipoprotein Recep-
`tor-Related Protein 1; mAb: Monoclonal Antibody; MDR: Multiple
`Drug Resistance; mg: Milligram; min: Minute; mL: Milliliter; MMT:
`Montmorillonite; MNP: Magnetic Nanoparticle; mPEG: Methoxy
`Poly[Ethylene Glycol]; MTD: Maximum Tolerated Dose; NC: Nano-
`capsule; NSCLC: Non-Small Cell Lung Cancer; ng: Nanogram; NMR:
`Nuclear Magnetic Resonance; NP: Nanoparticle; OSA: Octyl-Modified
`Bovine Serum Albumin; PACA: Poly[Alkyl Cyanoacrylate]; PAMAM:
`Poly[Amidoamine]; PbAE: Poly[β-Amino Ester]; PBCA: Poly[Butyl
`Cyanoacrylate]; PCL: Poly [ε-Caprolactone]; PE: Phosphatidyl Etha-
`nolamine; PEEP: Poly[Ethyl Ethylene Phosphate]; PEG: Poly[Ethylene
`Glycol]; PEG-DSPE: Polyethylene Glycol-Distearoylphosphatidyletha-
`nolamine; PEI: Polyethylenimine; PEO-b-PCL: Poly[Ethylene Oxide]-
`block-Poly[ε-Caprolactone]; PEO-PbAE: Poly[Ethylene Oxide]-Mod-
`
`ified Poly[β-Amino Ester]; PEO-PPO-PEO: Poly[Ethylene Oxide]-
`Poly[Propylene Oxide]-Poly[Ethylene Oxide]; PEtOz: Poly[2-Ethyl-
`2-Oxazoline]; PG: Poly[L-Glutamic Acid]; PGG: Poly[L-γ-Glutamyl-
`Glutamine]; P-gp: P-glycoprotein; PLA: Poly[L-Lactide]; PLGA:
`Poly[Lactic-Co-Glycolic Acid]; Pluronic P85: Poly[Oxyethylene-b-
`Oxypropylene-b-Oxyethylene]; PPEEA : Poly[2-Aminoethyl Ethylene
`Phosphate]; PVA: Poly[Vinyl Alcohol]; PX: Paclitaxel; Ref: Reference;
`RES: Reticuloendothelial System; RHAMM: Hyaluronan-Mediated
`Motility Receptor; RNA: Ribonucleic Acid; s.c.: Subcutaneous; SD:
`Standard Deviation; SEC: Size Exclusion Chromatography; siRNA:
`Small Interfering RNA; SLN: Solid Lipid Nanoparticle; SPAnNa: Poly
`[Aniline-co-Sodium N-[1-One-Butyric Acid] Aniline]; SSMM: Steri-
`cally Stabilized Mixed Micelle; t1/2: Half-Life; TEM: Transmission Elec-
`tron Microscopy; TPGS: D-α-Tocopheryl Polyethylene Glycol 1000
`Succinate; µg: Microgram; µL: Microliter; VIP : Vasoactive Intestinal
`Peptide; vs: Versus
`Paclitaxel and its Limitations
`Paclitaxel (PX), isolated from the bark of Pacific Yew (Taxus
`brevifolia), which was first discovered by Mrs. Monroe E. Wall and
`Mansukh C. Wani, is a white crystalline powder with the melting point
`
`*Corresponding author: Russell J. Mumper, Vice Dean and John A. McNeill
`Distinguished Professor, Center for Nanotechnology in Drug Delivery, Division
`of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy CB# 7355,
`100G Beard Hall, University of North Carolina at Chapel Hill, Chapel Hill, North
`Carolina 27599-7355, USA, Tel: +1-919-966-1271; Fax: +1-919-966-6919; E-mail:
`mumper@email.unc.edu
`Received January 17, 2013; Accepted February 15, 2013; Published February
`18, 2013
`Citation: Ma P, Mumper RJ (2013) Paclitaxel Nano-Delivery Systems: A
`Comprehensive Review. J Nanomed Nanotechol 4: 164. doi:10.4172/2157-
`7439.1000164
`Copyright: © 2013 Ma P, et al. This is an open-access article distributed under
`the terms of the Creative Commons Attribution License, which permits unrestricted
`use, distribution, and reproduction in any medium, provided the original author and
`source are credited.
`
`J Nanomed Nanotechol
`ISSN:2157-7439 JNMNT, an open access journal
`
`Volume 4 • Issue 2 • 1000164
`
`

`

`Citation: Ma P, Mumper RJ (2013) Paclitaxel Nano-Delivery Systems: A Comprehensive Review. J Nanomed Nanotechol 4: 164. doi:10.4172/2157-
`7439.1000164
`
`Page 2 of 16
`
`tolerated doses (MTD) of NPs are realized. It should be noted that, in
`general, the addition of polyethylene glycol (PEG) on the surface of NPs
`is required to avoid RES clearance [7]. Fourth, the pharmacokinetic
`profiles of the drug from NPs is improved, for example, increasing
`the half-life and tumor accumulation of PX. Last, but not the least, the
`surface of PX NP systems can be functionalized with active ligands
`for targeting purpose, which in-turn will further increase the tumor
`uptake and decrease the side effects of the drug. For more details about
`the advantages of NP-based drug delivery systems, please refer to the
`referenced review articles [8-12].
`Polymeric Nanoparticles
`A summary of PX-loaded polymeric NPs is shown in Table 1.
`Poly (lactic-co-glycolic acid) (PLGA) Nanoparticles
`PLGA is one of the most widely used biodegradable co-polymers
`for the development of nano-delivery systems because it undergoes
`hydrolysis in the body and produces non-toxic products of lactic acid
`and glycolic acid, and eventually carbon dioxide and water. Since
`the body effectively deals with both degradants, the systemic toxicity
`associated with PLGA is minimal.
`PX-loaded PLGA NPs have been engineered by different methods,
`such as o/w emulsion-solvent evaporation [13,14], nanoprecipitation
`[15] and interfacial deposition methods [16]. In most cases, PX was
`released from PLGA NPs in a biphasic pattern with a fast initial release
`during the first 1-3 days followed by a slow and continuous release
`[13,14,16-18]. PX-encapsulated PLGA NPs demonstrated enhanced in
`vitro cytotoxicity as compared to free PX in various cancer cell lines,
`such as glioma C6 cells [17], NCI-H69 human small cell lung cancer
`cells [16], MCF-7 [18] and HeLa cells [15,18]. Furthermore, in vivo PX-
`loaded PLGA NPs showed significantly better tumor growth inhibition
`effect with transplantable liver tumors [15].
`The surface of PLGA NPs was modified for improved drug
`delivery. Chitosan-coated PLGA NPs exhibited slower in vitro drug
`release compared to non-coated PLGA NPs and significantly changed
`the zeta potential from the negative charge of -30.1 mV for PLGA
`NPs alone to the positive charge of 26 mV, which facilitated drug
`cell uptake than uncoated NPs [19]. Chakravarthi et al. [20] showed
`a 4-10-fold increase in cellular association of PX and enhanced
`cytotoxicity when applied chitosan-modified PLGA NPs. In addition to
`chitosan, didodecyldimethylammonium bromide (DMAB), a cationic
`surfactant, was also applied to absorb on the surface of PX-loaded NPs
`by electrostatic attraction. Upon the addition of DMAB, the negatively-
`charged NPs shifted to become positively-charged [21]. This DMAB
`modified PX-incorporated PLGA NPs completely inhibited intimal
`proliferation in a rabbit vascular injury model [22].
`PLGA NPs were also optimized using different emulsifiers. It is
`known that the employed emulsifiers/stabilizers could have strong
`influence on the properties of produced NPs, such as morphology,
`particle size, drug entrapment efficiency, in vitro release behavior, cellular
`uptake, in vitro cytotoxicity, pharmacokinetics and biodistribution, and
`as a consequence therapeutic efficacy [23]. Poly (vinyl alcohol) (PVA)
`is the most commonly used emulsifier. Other emulsifiers were also
`applied in PLGA NPs. For example, when d-α-tocopheryl polyethylene
`glycol 1000 succinate (TPGS) was utilized in PX-loaded PLGA NPs
`as the surfactant emulsifier, the PLGA/TPGS NPs could achieve drug
`encapsulation efficiency of 100% [24], better controlled drug release
`kinetics [25], and enhanced cellular uptake and cytotoxicity [26]
`compared to that of PVA-emulsified PLGA NPs. The TPGS-emulsified
`
`of ~210°C (Figure 1). It is one of the most effective chemotherapeutic
`drugs and is mainly used to treat lung, ovarian, and breast cancer, etc [1].
`The mechanism of action of PX is to promote and stabilize microtubules
`and inhibit late G2 or M phases of cell cycle, thereby causing the cell
`death. The major limitation of PX is its low water solubility (~0.4 µg/
`mL); thus, it is formulated in organic solvents of polyoxyethylated
`castor oil (Cremophor EL) and dehydrated ethanol (50/50, v/v) under
`the trademark “Taxol”. However, Cremophor EL is known to cause
`serious side effects, such as hypersensitivity reactions [2]. As a result,
`prolonged infusion time and pretreatments are required. Moreover,
`the presence of Cremophor EL alters the pharmacokinetic profile of
`PX in vivo which was described as unpredictable non-linear plasma
`pharmacokinetics when PX was formulated in Cremophor EL [3]. In
`addition, PX is a substrate of P-glycoprotein (P-gp), which actively
`pumps PX out of the cells and induces drug resistance [4]. To overcome
`this problem, several P-gp inhibitors, such as verapamil [5] and PSC 833
`[6], were co-administered with Taxol but the results were disappointing
`due to their toxicity and/or alteration of PX pharmacokinetics and
`biodistribution. Nano-delivery systems are promising vehicles in drug
`delivery because they improve solubility of hydrophobic drugs, such as
`PX, and generally have low toxicity as well. Abraxane®, a PX albumin-
`bound NP formulation with the particle size of ~130 nm, was approved
`by the FDA in 2005 for the treatment of metastatic breast cancer.
`This formulation had demonstrated some advantages in terms of
`reduced toxicity compared to Taxol. In addition, the total dose can be
`administered within 30 min without pretreatment. However, whether
`Abraxane® could improve survival and address P-gp-mediated drug
`resistance is still unclear. Therefore, the alternative PX formulations
`are still in demand. In this review, various nanoparticle (NP) systems
`for the delivery of PX will be addressed, such as polymeric NPs, lipid-
`based NP formulations, polymer conjugates, inorganic NPs, carbon
`nanotubes, nanocrystals, cyclodextrin NPs, etc.
`Advantages of Nanoparticle-Based Paclitaxel Delivery
`Systems
`Nanoparticle delivery systems have attracted increasing attention
`in recent years, especially for cancer therapies. As an effective
`chemotherapeutic agent, PX has been formulated in various nano-
`delivery systems which have several advantages over the standard-of-
`care therapy. First, the aqueous solubility of PX can be greatly enhanced
`when it is conjugated with water-soluble polymers, or encapsulated
`into lipid-based NPs. Second, they are small in size (several to several
`hundred nanometers in diameter), which enables the preferential
`delivery of PX into the tumor site due to the enhanced permeability
`and retention (EPR) effect. Third, they can escape the recognition
`of reticuloendothelial system (RES) in healthy tissues and therefore
`reduce the side effects of the drug. As a consequence, higher maximum
`
`O
`
`O
`
`O
`
`OH
`H
`
`O
`
`NH
`
`O
`
`O
`
`O
`
`H
`
`O
`
`OO
`
`O
`
`HO
`
`OH
`
`Figure 1: Chemical Structure of PX.
`
`J Nanomed Nanotechol
`ISSN:2157-7439 JNMNT, an open access journal
`
`Volume 4 • Issue 2 • 1000164
`
`

`

`Citation: Ma P, Mumper RJ (2013) Paclitaxel Nano-Delivery Systems: A Comprehensive Review. J Nanomed Nanotechol 4: 164. doi:10.4172/2157-
`7439.1000164
`
`Polymer
`
`PLGA
`
`PCL
`
`PLA
`
`Chitosan
`
`Gelatin
`
`HA
`
`PBCA
`
`Albumin
`
`HPG
`PEG-PE
`
`NP Preparation Method
`emulsion-solvent evaporation
`nanoprecipitation
`interfacial deposition
`emulsion-solvent evaporation
`emulsion-solvent evaporation
`emulsion-solvent evaporation
`emulsion-solvent evaporation
`emulsion-solvent evaporation
`emulsion-solvent evaporation
`emulsion-solvent evaporation
`emulsion-solvent evaporation
`nanoprecipitation
`solvent displacement
`emulsion-solvent evaporation
`
`modified solvent displacement
`
`emulsion and evaporation
`
`solid dispersion
`modified nanoprecipitation
`co-solvent extraction
`
`dialysis
`
`Modification
`―
`PLGA, PLGA-PEG, PCL-PEG
`Poloxamer 188
`TPGS (emulsifier)
`DLPC (emulsifier)
`DPPC (emulsifier)
`chitosan
`DMAB
`MMT
`MMT, HER2 (targeting)
`RGD (targeting)
`Pluronic P85, transferrin (targeting)
`PEO-PCL
`PCL-pluronic F68
`PCL-pluronic F68,
`DMAB
`mPEG-PCL,
`Angiopep (targeting)
`mPEG-PCL
`PVP-b-PCL
`PEG-PCL
`PEG-PCL,
`folic acid (targeting)
`dialysis
`PCL-g-PVA
`dialysis
`PEtOz-PCL
`dialysis
`PCL-PEEP, galactosamine, (targeting)
`emulsion-solvent evaporation
`mPEG-PCL-PPEEA
`thin film
`PLA-PEG (diblock)
`solvent evaporation
`PLA-PEO (star-branch)
`solvent evaporation
`PVA-PEG
`solvent evaporation
`Poly(γ-glutamic acid), galactosamine (targeting)
`solvent evaporation
`PLA-PEG-PLA, PEG-PLA-PEG
`dialysis
`cholanic acid
`dialysis
`oligomer
`emulsion-solvent evaporation
`glyceryl monooleate
`dialysis
`mPEG, cholesterol
`―
`N-acetyl histidine
`ultrasonication
`stearic acid, glutaraldehyde
`desolvation
`―
`desolvation
`―
`dialysis
`oligomer
`miniemulsion
`pluronic F127
`dialysis
`chitosan
`polymerization
`surfactants (dextran 70, cholesterol, PVA, and lecithin)
`high-pressure homogenization
`―
`―
`CREKA and LyP-1, peptides (targeting)
`desolvation
`folic acid (targeting)
`dialysis
`octaldehyde
`solvent evaporation
`PEG, PEI
`EPC, solid triglycerides, cationic Lipofectin lipids
`solvent evaporation
`Table 1: Summary of PX-loaded Polymeric NPs. (*EE=Entrapment Efficiency).
`
`Page 3 of 16
`
`References
`[14]
`[15]
`[16]
`[24]
`[28]
`[29]
`[19]
`[21]
`[30]
`[31]
`[32]
`[33]
`[63,64]
`[72]
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`[67,68]
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`
`Status
`in-vitro
`in-vivo
`in-vitro
`in-vitro
`in-vitro
`in-vitro
`in-vitro
`in-vivo
`in-vitro
`in-vitro
`in-vivo
`in-vivo
`in-vivo
`in-vivo
`
`in-vivo
`
`in-vivo
`
`in-vivo
`in-vivo
`in-vivo
`
`in-vitro
`
`in-vitro
`in-vitro
`in-vitro
`in-vivo
`in-vivo
`in-vitro
`in-vitro
`in-vivo
`in-vivo
`in-vivo
`in-vivo
`in-vitro
`in-vivo
`in-vitro
`in-vitro
`in-vivo
`in-vivo
`in-vitro
`in-vitro
`in-vivo
`in-vitro
`approved
`in-vivo
`in-vitro
`in-vitro
`in-vivo
`in-vivo
`
`% EE*
`85
`70
`>90
`100
`15-56
`34-45
`75-79
`47
`~50
`~50
`60-65
`70-76
`>95
`84
`
`76-88
`
`90
`
`98
`85
`―
`
`―
`
`―
`5-76
`―
`>90
`65
`6-56
`20-62
`50-54
`14-31
`92
`97
`98-100
`70
`―
`94-99
`> 80
`90
`―
`80
`90
`60-80
`―
`―
`95
`90
`―
`~100
`
`PLGA NPs achieved 10-fold greater bioavailability than Taxol after
`oral administration [27]. Phospholipids were also used as natural
`emulsifiers in PLGA NPs, such as 1,2-dilauroylphosphatidylcholine
`(DLPC) [28] and dipalmitoyl-phosphatidylcholine (DPPC) [29]. Both
`of the emulsifiers demonstrated greater benefits compared to PVA.
`Montmorillonite (MMT) was also incorporated into PX-loaded PLGA
`NPs as both of matrix component and co-emulsifier. The addition of
`MMT did not change particle size, drug entrapment efficiency, or the in
`vitro drug release from PLGA NPs. Importantly, the PX-loaded PLGA/
`
`MMT NPs enhanced drug cellular uptake over that of pure PLGA NPs
`by 57-177% and 11-55% in Caco-2 and HT-29 cells, respectively [30].
`The PX-loaded PLGA/MMT NPs were further decorated with human
`epidermal growth factor receptor 2 (HER2) antibodies for targeting
`purpose, and these targeted NPs exhibited a 12.7-fold enhanced
`cytotoxicity compared to non-targeted NPs in SK-BR-3 cells [31].
`Other targeting ligands, such as RGD [32] and transferrin [33-35],
`have also been conjugated to PX-encapsulated PLGA NPs for better
`antitumor efficacy. For example, PX-incorporated PLGA NPs with
`
`J Nanomed Nanotechol
`ISSN:2157-7439 JNMNT, an open access journal
`
`Volume 4 • Issue 2 • 1000164
`
`

`

`Citation: Ma P, Mumper RJ (2013) Paclitaxel Nano-Delivery Systems: A Comprehensive Review. J Nanomed Nanotechol 4: 164. doi:10.4172/2157-
`7439.1000164
`
`transferrin ligand showed 5-fold enhanced cytotoxicity over that
`of non-targeted NPs or Taxol. The mice treated with targeted NPs
`demonstrated complete tumor inhibition and significantly prolonged
`survival compared to all controls after intratumoral injection in a PC3
`prostate cancer mouse model [34].
`Poly(lactide) (PLA) Nanoparticles
`PLA is another widely used matrix material for polymeric NP
`preparation because of its biodegradable and safe properties. Methoxy
`poly(ethylene glycol)-poly(lactide) co-polymer (mPEG-PLA) was
`synthesized and incorporated into the NPs to provide long circulating
`properties. The in vitro cytotoxicity of these NPs increased by 33.3-fold
`over that of Taxol after 24 h in MCF-7 cells. In vivo pharmacokinetic
`studies demonstrated the AUC and half-life of PX mPEG-PLA NPs in
`rat plasma were 3.1- and 2.8-fold greater than that of Taxol, respectively
`[36,37]. PX-loaded NPs with PLA and mPEG-PLA at various ratios of
`100/0, 75/25, 50/50, 25/75, and 0/100 were evaluated. It was found that
`as the mPEG-PLA component in the blend increased, the particle size
`of NPs and the glass transition temperature of PLA decreased, while
`the zeta potential of NPs and in vitro drug release increased [38]. Co-
`polymers of PLA/Tween 80 were synthesized and PX-loaded PLA/
`Tween 80 NPs were shown to be about 3-fold more toxic than PX-
`loaded PLGA NPs in glioma C6 cells [39]. TPGS was also utilized as an
`emulsifier in PLA NPs. The Feng group [40] synthesized PLA-TPGS
`co-polymers using a ring-opening polymerization method. Compared
`to PX-loaded NPs, the PLA/TPGS NPs showed 1.8- and 1.4-fold
`enhanced cellular uptake of PX in HT-29 and Caco-2 cells, respectively.
`The IC50 value of PLA/TPGS NPs was also found to be 40% lower than
`that of Taxol in HT-29 cells [41]. In vivo this PX-loaded PLA/TPGS NP
`formulation achieved a 27.4- and 1.6-fold greater half-life and AUC,
`respectively, in a xenograft tumor model when compared to Taxol
`[42]. PX-loaded PLA/TPGS NPs with various ratios of PLA and TPGS
`were evaluated, and the results demonstrated that the PLA/TPGS ratio
`had little effect on particle size. However, PLA/TPGS NPs with PLA/
`TPGS ratio of 89/11 were the optimized formulation in terms of drug
`entrapment efficiency, cellular uptake, and in vitro cytotoxicity [43].
`Folate-decorated PX-loaded PLA-TPGS NPs were further formulated
`to achieve even better therapeutic effect [44,45]. Other targeted PX-
`loaded PLA NPs, such as HER2 [46], biotin and folic acid [47], were
`also reported to greatly improve efficacy both in vitro and in vivo.
`PLA co-polymer micelles have also been reported for PX delivery
`[48-53]. For example, PX-loaded PEG-b-PLA micelles were prepared
`and the mechanism of action was investigated. It was found that the
`micelles first interacted with cell membranes and then the loaded PX
`was released. After that, PX was internalized into the cells by lipid/
`raft/caveolae-mediated endocytosis pathway. In this way, PEG-b-
`PLA micelles were able to overcome multiple drug resistance (MDR)
`which was confirmed by the increased cellular uptake of PX in resistant
`A2780/T cells. The results also suggested PEG-b-PLA micelles could
`inhibit P-gp efflux [49]. Paxceed® is a polymeric micelle formulation
`where PX is encapsulated in PLA-b-mPEG diblock co-polymers. The
`micellar formulation was found to be more efficacious than Taxol at
`the maximum tolerated dose (MTD) upon intraperitoneal injection
`in an MV-522 lung tumor bearing mouse model [54]. Currently,
`Paxceed® is in phase II clinical trials [55]. Genexol-PM remains the
`most successful PX micellar formulation to date, which is composed
`of PLA-b-PEG diblock co-polymers [56]. A preclinical in vivo study
`with Genexol-PM was found to have 3-fold increased MTD and 2-3-
`fold higher drug concentration in various tissues and more importantly
`in tumors, compared to Taxol in nude mice. The in vivo antitumor
`
`Page 4 of 16
`
`efficacy of Genexol-PM was also significantly improved [57]. In phase
`I clinical studies, the MTD dose was determined to be 180 mg/m2. The
`plasma AUC and Cmax increased by 3- and 4-fold, respectively, when
`the dose increased from 80 to 200 mg/m2 [58], which suggested the
`pharmacokinetics of Genexol-PM were dose-proportional. In phase
`II clinical studies, Genexol-PM was found to be safe and effective in
`patients with metastatic breast or advanced pancreatic cancer [59,60].
`Phase III clinical studies are currently in process.
`Triblock co-polymers of PLA-PEG-PLA and PEG-PLA-PEG
`were synthesized as carriers for PX. The results demonstrated that
`the drug release from PEG-PLA-PEG micelles was slower than from
`PLA-PEG-PLA micelles, and PEG contents in micelles influenced
`the stealth properties of the micelles. Both of micelles showed 4-fold
`decreased monocyte cell uptake compared to PLA micelles [52,53]. In
`another study, a four-armed (star-branched) co-polymer of PLA and
`PEO was synthesized. Compared to di- and tri-block co-polymers,
`the star-branched micelles exhibited better controlled and more
`complete release manner over 2 weeks. Furthermore, the star-shaped
`micelles had smaller particle size which had the potential to take more
`advantages of the EPR effect in cancer therapy [48].
`In addition to PEG-modified PLGA micelles, PX-incorporated
`PVP-b-PLA micelles were prepared by Gaucher et al. [50] by an o/w
`emulsion solvent evaporation method. The cryoprotectant property
`of PVP allowed the same particle size upon reconstitution after
`lyophilization, while PEG-modified PEG-b-PLA micelles did not.
`For targeting purpose, a galactosamine targeted PX-loaded micelle
`formulation composed of poly(γ-glutamic acid) and PLA was
`developed. The targeted NP formulation showed the most significant
`antitumor efficacy compared to other controls and importantly more
`drug accumulation in tumors was observed in hepatoma tumor-
`bearing nude mice [51].
`Poly(ε-caprolactone) (PCL) Nanoparticles
`Deshpande et al. [61] developed poly(ethylene oxide)-modified
`poly(ε-caprolactone) (PEO-PCL) NPs for co-delivery of PX and C6-
`ceramide (an apoptotic signaling molecule) to overcome MDR. The
`prepared PEO-PCL NPs had high drug entrapment efficiency of >95%
`with PX and C6-ceramide drug loading of 10% (w/w). The particle size
`of the NPs was ~270 nm in diameter. In resistant human ovarian cancer
`SKOV3TR cells, PX and C6-ceramide loaded PEO-PCL NPs showed
`100-fold enhanced cytotoxicity compared to free PX [62]. In vivo PEO-
`PCL NPs demonstrated remarkable tumor growth inhibition in both
`wild-type SKOV3 and resistant SKOV3TR xenograft mouse models
`compared to all the controls. The results indicated the combination of
`PX and C6-ceramide incorporated into PEO-PCL NPs overcame MDR
`in ovarian cancer [63]. The combination of PX and tamoxifen loaded
`PEO-PCL NPs was also evaluated both in vitro and in vivo. In vitro this
`formulation lowered the IC50 by 10- and 3-fold in SKOV3 and SKOV3TR
`cells, respectively, when compared to free PX. The in vivo PEO-PCL
`NPs significantly enhanced antitumor efficacy and no acute toxicity
`was observed [64]. Later, polymeric NP systems for the co-delivery of
`both PX and P-gp silencing siRNA were developed. In order to do that,
`poly(ethylene oxide)-modified poly(β-amino ester) (PEO-PbAE) and
`PEO-PCL NPs were formulated to encapsulate P-gp silencing siRNA
`and PX, respectively. The co-administration of P-gp silencing siRNA-
`loaded PEO-PbAE NPs and PX-loaded PEO-PCL NPs completel