Paclitaxel Drug Delivery Systems: Focus on Nanocrystals’ Surface Modifications
3. PTX Formulations
4. Drug Delivery of PTX
4.3.1. Solid Lipid Nanoparticles
4.3.2. Polymeric Nanoparticles
Poly Lactic-co-Glycolic Acid (PLGA)
4.4. Prodrug Approach
5. PTX Nanocrystals
6. Future Aspects
7. Conclusions and Remarks
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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|PTX NC||Method of Preparation||The Models Used and the Reference or Control Formula||Benefits, Aims, and Other Notes||Refs.|
|Albumin-coated PTX-NC |
|NC crystallized in the medium containing Pluronic F-127 and then coated with albumin |
|The new formula was compared to Abraxane and solvent-dissolved PTX |
In vitro models including Biolayer interferometry analysisCell culture models: J774A.1 macrophages and SPARC+ B16F10 melanoma cells
In vivo model: mouse model of B16F10 melanoma
|High drug loading (90%) and serum stability |
More stability in undiluted serum.
Less interaction with serum proteins.
In cell culture studies, demonstrated suitable cell interaction profiles (depressed uptake by macrophages and great uptake by melanoma cells).
In the in vivo studies, exhibited prolonged plasma t1/2 and superior accumulation in tumors by about 1.5 and 4.6 times, respectively.
Exhibited superior antitumor efficacy.
|Surface modified PTX-NCs with apo-transferrin (Tf) or hyaluronic acid (HA)||PTX NCs were prepared by the nanoprecipitation |
Method, and then the surface was modified by grafting with Tf or HA
|The new formula was compared to PTX-NC and pure PTX drug |
In vitro models: drug release in PBS with or without tween 80
Cell culture models: HaCaT normal cells and MCF-7 cancer cells
|PTX release was faster. |
Improve the cellular uptake, permeability, and cell growth inhibition (60%) against the cancer cells.
The effect on the normal cells was inferior.
Provide targeted delivery to cancer cells.
|Hyaluronic acid (HA) coated PTX NCs||The NCs were prepared by the top-down method using homogenization||The new formula was compared to Taxol® and heparin-coated PTX NCs |
In vitro models: 2D monolayer and 3D spheroids
Cell culture models: MDA-MB 231 cells
In vivo model: LA-7 tumor-bearing rat model
|Exhibited superior in vitro efficacy. |
HA-PTX NCs incur receptor-mediated endocytosis by binding to CD44 receptors.
The in vivo studies indicated significantly prolonged blood circulation time of PTX.
Exhibited superior efficacy with reduced lung metastasis and toxicity.
|PEGylated PTX NCs||The NCs were prepared by the antisolvent precipitation method combined with probe sonication||The new formula was compared to PTX NCs and Taxol® |
In vivo model: breast cancer xenografted mice model and a model of lung tumor metastasis quantified by the luciferase activity
|Superior stability under both storage and physiological conditions. |
In vivo studies showed significant improvement of the antitumor activity in facing in situ or metastatic tumors.
|PEGylated polyelectrolyte multilayer-coated PTX NCs||The layer-by-layer method was used to coat PTX NCs with alternating |
layers of oppositely charged polyelectrolytes, utilizing a PEGylated copolymer as the upper layer, and PTX NCs were prepared by a wet milling approach
|The new formula was compared to Abraxane and PTX NCs |
In vitro models: physiologically relevant media and human RBC hemolysis
Cell culture models: HT-29 cells
In vivo model: NMRI-nu mice bearing HT-29 subcutaneous xenografts
|Slowed down the dissolution. |
Offered colloidal stability in physiologically simulated media.
Showed no innate effect on cell viability using HT-29 cells.
No hemolytic activity was detected.
Quickly eliminated from the bloodstream and accumulated in the liver and spleen (mononuclear phagocyte organs).
Poor tumor accumulation.
|PTX NCs modified with PEG and folic acid (FA)(PTX NCs-PEG-FA)||PTX NCs were prepared by thin-film hydration method, which is a bottom-up method, and then modified with both PEG and |
FA derivatives using thin-film hydration technique
|The new formula was compared to Taxol®, PTX NCs, and PTX NCs-PEG |
In vitro models: plasma
Cell culture models: 4T1 breast cancer cells
In vivo model: PK rat model and 4T1 orthotopic breast cancer-bearing nude mice
|More size stability in plasma. |
Improved cellular uptake and growth inhibition in cells.
An in vivo pharmacokinetic study showed a significant increase in the circulation of PTX.
In vivo cancer model showed that it significantly enhanced the accumulation of PTX in the tumor and effectively inhibited tumor growth.
|Surface hybridization of PTX NCs by DSPE-PEG 2000||PTX NCs were prepared by anti-solvent method, and DSPE-PEG 2000 was incorporated by hybridization||The new formula was compared to PTX solution and PTX NCs |
In vitro models: in vitro release study
In vivo model: PK rats’ model
|Similar size with an increased negative charge. |
The in vitro study showed that the release of PTX was significantly slower.
The pharmacokinetics studies showed a greater area under the curve (AUC) and a lower clearance rate.
|Cube-shaped PTX NC prodrug with surface functionalization of SPC and MPEG-DSPE||PTX was labeled with fluorophore conjugate 4-chloro-7-nitro-1, 2, 3-benzoxadiazole (NBD-Cl) (PTX-NBD), which was synthesized by a nucleophilic substitution reaction of PTX with NBD-Cl in high yield. The PTX-NBD NCs were prepared by the anti-solvent method followed by surface functionalization of SPC and MPEG-DSPE.||The new formula was compared to free PTX-NBD and the sphere-shaped PTX-NBD nanocrystals with surface functionalization of SPC and MPEG-DSPE ([email protected] NSs) |
Cell culture models: HeLa cells
|The cube-shaped [email protected] NCs exhibited better drug loading and stability properties. |
It showed a remarkable decrease in burst release, efficiently enhanced cellular uptake, and had a better ability to kill cancer cells in vitro using HeLa cells.
These NCs can be useful for cell imaging and chemotherapy.
PTX with positively charged poly(allylamine hydrochloride)
|Nano-precipitation method (bottom-up approach) was employed to prepare PTX NCs, and the surface-modified NCs were obtained by an absorption method with the positively charged polymer||The new formula was compared to pure PTX, PTX NCs, and negatively charged poly (sodium 4-styrene sulfonate) PSS PTX NCs |
In vitro models: PBS (pH 7.4) containing 0.5% (w/v) tween 80 and bovine serum albumin (BSA)
Cell culture models: A549 cells
|Higher drug release.|
Stronger interaction with bovine serum albumin.
Greater cellular internalization, uptake, and cytotoxicity.
|A non-covalent transferrin-stabilized PTX NCs||The NCs were prepared by the antisolvent precipitation method augmented by sonication||The new formula was compared to PTX solution, PTX NCs, and Taxol® |
Cell culture models: human KB epidermal carcinoma cells and SKOV-3 ovarian cancer cells
In vivo model: mice inoculated with KB cells
|The in vivo efficacy studies on KB-bearing mice showed a significantly superior tumor inhibition rate compared with PTX NCs and less efficacy than Taxol, but with a better toxicity profile. However, in cellular models, it showed similar efficacy 72 h after treatment.|||
|PTX NCs stabilized by D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)||The NCs were prepared by three-phase nanoparticle engineering technology (3PNET)||The new formula was compared to Taxol® and PTX/Pluronic F127 (F127) NCs |
Cell culture models: P-glycoprotein-overexpressing PTX-resistant (H460/TaxR) cancer cells
In vivo model: PK using CD-1 mice
|The greater the amount of TPGS in the formula, the greater cytotoxicity and cellular internalization. |
TPGS PTX NCs demonstrated a significantly sustained and prolonged in vitro release pattern.
PK studies indicated more rapid clearance. However, they were more effective in promoting the accumulation of PTX in drug-resistant tumors.
|Herceptin (HCT)-functionalized PTX NCs||PTX NCs were prepared by sono-precipitation approach, and then HCT was coated, applying a facile non-covalent technique||The new formula was compared to PTX NCs and PTX powder |
In vitro models: release study
Cell culture models: HER2-positive breast cancer cell lines
|Exhibited a sustained release pattern comparable to PTX NCs. |
Demonstrated a higher binding affinity, greater cell-specific internalization, and inhibition of growth to HER2-positive breast cancer cell lines.
|PTX-NCs coated with Pluronic® F68 (PEG-PPG-PEG block polymer)||The NCs were prepared by the anti-solvent method||The new formula was compared to Taxol® and PTX NCs |
In vivo model: tumor-bearing (HT-29 and KB cells) mice and female nude outbred mice
|These NCs exhibited similar or better antitumor efficacy and lower toxicity in comparison with Taxol. |
The in vivo study showed a significant enhancement in the blood circulation of PTX and accumulation in tumor tissue. However, the definite amount that reached the tumor was still minimal for the administered dose.
The maximum amount of the coated NCs was significantly obtained in the liver compared with the other organs relative to the uncoated PTX NCs.
|Triphenylphosphonium (TPP+)-stabilized PTX NCs |
(TPP+ PTX NCs)
|Precipitation-resuspending method||The new formula was compared to free PTX and unmodified PTX NCs |
In vitro cell culture models: 2D monolayer and 3D multicellular spheroids (MCs) of MCF-7 cells and MCF-7/ADR cells
|A mitochondria-targeted system was developed. |
Showed the strongest cytotoxicity that was associated with a reduction in mitochondrial membrane potential.
Showed greater penetration and superior growth inhibition.
|Platelet membrane-coated or cloaked PEG-PTX NCs |
|The modified emulsion-lyophilized crystallization method||The new formula was compared to PTX NCs |
Platelet aggregation was examined using a spectrophotometric method
In vitro drug releasee
Cell culture models: 4T1 breast cancer cells
In vivo model: BALB/c mice injected with 4T1 cells model
|Minor risk of thrombus formation after injection was observed. |
Higher cellular uptake and greater cytotoxicity.
In vivo studies showed the ability to deliver a higher dose of the drug and target the site of the coagulation (surgery or vascular disrupting), which improved the antitumor efficacy and decreased toxicities.
|RGD peptide -PEGylated PTX NCs coated by polydopamine (PDA) |
|The NCs were prepared using modified antisolvent–sonication method||The new formula was compared to free PTX, PTX NCs, PTX NCs-PEG, and PTX NCs-PDA-PEG |
In vitro models: plasma for size stabilityCell culture models: A549 lung cancer cell line
In vivo model: nude mice A549 bearing cancer model
|More size stability in plasma. |
Showed superior cellular uptake, growth inhibition, and cytotoxicity on A549 lung cancer cell line.
In vivo demonstrated significantly greater accumulation in the tumor and slower tumor growth.
|PTX and lapatinib (LAPA) composite nanocrystals with PDA and PEG modification([email protected])||PEG coat was introduced into the cNC via PDA) coat to get PEGylated composite NCs ([email protected]). The NCs were prepared using the bottom-up method or precipitation-resuspending method.||The new formula was compared to free PTX and unmodified PTX NCs |
In vitro models: plasma and blood
Cell culture models: MCF-7/ADR cancer cells
|[email protected] had optimum size and stability. |
The in vitro release study showed that both PTX and LAPA were released completely from [email protected] in 3 days, while only 30% of the drug was released from bulk drugs or unmodified NCs.
Showed negligible hemocytolysis and improved therapeutic effect on MCF-7/ADR through endocytosis of whole NCs.
|PTX NC||Method of Preparation||The Models Used and the Reference or Control Formula||Benefits, Aims, and Other Notes||Ref.|
|Pluronic-grafted chitosan as a stabilizer for PTX NC |
(Pl-g-CH PTX NCs)
|A novel Pluronic-grafted chitosan copolymer was established and then utilized as a functional stabilizer for PTX NCs. Generally, the NCs were prepared using a high-pressure homogenizer.||The new formula was compared to Taxol® |
Cell culture models: Caco-2 cells and B16 F10 murine melanoma cells
In vivo model for oral PK evaluation: Wistar ratsIn vivo model for efficacy study: healthy Balb/C mice injected with B16 F10 murine melanoma model
|Improving intra-cellular accumulation. |
Improving the absorption by the transcellular and paracellular routes.
Showed a P-gp inhibitory property.
The in vivo model demonstrated more anti-tumor efficacy and growth reduction after oral delivery, and this was related to the enhancement in the systemic circulation as both the absorption and bioavailability were improved significantly.
|PTX NCs stabilized by tween 80 or low molecular weight synthetic polymer sodium polystyrene sulfonate (PSS)||The top-down method was performed using a microfluidizer as a high-pressure homogenizer that was used to prepare the NCs without using any organic solvent||The new formula was compared to formulas stabilized with high molecular weight polymers glycol chitosan (GC) and sodium alginate (SA), as well as with PTX solution and PTX-NCs |
Cell culture models: MCF7 and MDA-MB breast cancer cell lines
In vivo model: PK in male Wistar rat model
|The prepared NCs were more suitable, efficient, and exhibited a considerable increase in the dissolution rate, which indicated an enhancement in its bioavailability. |
The in vitro cell culture study showed more efficiency and potency in killing and inhibiting the growth of the cancer cells.
In vivo pharmacokinetic studies demonstrated a considerable increase in AUC0–t, Cmax, and MRT and a decrease in Tmax.
|Transferrin (TF)-modified PTX NCs||PTX NCs were prepared using the precipitation–resuspension method||The new formula was compared to Taxol® and unmodified PTX NCs |
In vitro models: in situ intestinal perfusion study
Cell culture models: Caco-2 cells and MCF-7 cancer cells
In vivo model: PK Sprague Dawley rat model
|Showed an enhancement of cellular monolayer penetration. |
Had superior suppression in MCF-7 cell growth.
Showed an enhancement of intestinal absorption.
The pharmacokinetic studies also demonstrated greater Cmax and AUC than both PTX NCs and Taxol® while having the lowest tmax.
|Poly(sodium pstyrenesulfonate) (PSS)-modified PTX NCs||Not mentioned||In vitro models: interactions with biomolecules in oral delivery pathways |
Cell culture models: Caco-2 cell lines
|Suitable mono-dispersion and stability in the gastrointestinal tract (GIT) environments for at least 24 h. |
No substantial interactions with pepsin or trypsin enzymes were detected in the GIT environments.
PSS-modified PTX NCs passed through the mimical intestinal epithelial cell (Caco-2 cell lines) with about 25% transmittance. However, the concentration of the NCs should be controlled to avoid toxic effects on the cells.
|PTX NC||Route of Administration||Method of Preparation||The Models Used and the Reference or Control Formula||Benefits, Aims, and Other Notes||Ref.|
|PTX NC-loaded PECT hydrogels||Local delivery and peritumoral administration||PTX NCs were prepared by three-phase nanoparticle engineering technology (3PNET), while PTX-NC-based PECT (PTX-NC-PECT) gel was prepared based on the “cold” method||The new formula was compared to a nanoparticle-based system (PTX-NP-PECT) and controlled hydrogel of Pluronic® F127 |
In vitro models: release study
In vivo model: MCF-7 tumor-bearing mouse models
|High loading capacity of the drug. |
In vitro release was more effective and homogeneous.
In vivo near-infrared fluorescence (NIRF) imaging indicated the ability to maintain the payloads of 1,1-dioctadecyltetramethyl indotricarbocyanine iodide (DiR) at a peri-tumoral site for about 21 days.
Exhibited the most complete release system with the greatest anti-tumor efficacy and apoptosis effect.
|Silica-coated PTX NCs |
|Intra-peritoneal (IP)||Precipitation–resuspending |
|The new formula was compared to uncoated PTX-NC or Abraxane |
Cell culture model: neural stem cells and OVCAR-8 cells
In vivo model: athymic nude mice which inoculated with 2 M OVCAR-8.eGFP.ffluc human ovarian cancer cells
|More effective in loading neural stem |
In vivo studies showed that loaded NSCs preserved their migratory ability and, for low PTX dose, were more effective against ovarian tumors.
|Poly-tannic acid-coated PTX NCs |
|Intertumoral injection||The NCs were prepared using the thin-film hydration method followed by probe sonication||The new formula was compared with or without laser irradiation to PTX |
Cell culture models: 4T1, A549, and HepG2 cells
In vivo model: 4T1 tumor-bearing mice
|PTX NCs were prepared to act as a chemo-therapeutic agent and poly-tannic acid (pTA)-coated PTX NCs in the presence of Fe3+ acting as a potential agent for photothermal therapy (PTT). |
The cellular uptake was significantly improved.
A synergistic effect with laser irradiation was observed.
Demonstrated mild photothermal effect in vivo and the greatest effect in tumor inhibition upon laser irradiation.
|PTX NC with F127 hydrogel||Intertumoral injection||Precipitation–resuspending |
method. The cold method was used for hydrogel preparation.
|The new formula was compared to PTX or PTX microcrystal-based hydrogels |
In vitro erosion of the hydrogels and drug release
In vivo model: 4T1 tumor-bearing BALB/c mice
|PTX NCs gel offered optimum properties with high drug loading combined with moderate drug release and erosion profiles. |
Superior anti-tumor efficacy in 4T1 tumor-bearing BALB/c mice.
|In situ cross-linkable hydrogel depot containing PTX NCs||Intraperitoneal (IP)||Anti-solvent and temperature-induced crystallization method||The new formula was compared to Taxol® and microparticulate PTX precipitates (PPT) |
Cell culture models: SKOV3 cells
In vivo model: healthy Balb/c mice for toxicity studies and Balb/c mice (SKOV3-Luc) cell-bearing mice for the efficacy study
|Superior killing efficiency and more toxicity in SKOV3 cell line. |
The in vivo study indicated improved dissolution, cellular uptake, and lower maximum tolerated dose.
It also showed that a single IP dose was sufficient in extending the survival of tumor-bearing mice.
|PTX-NCs combined with niclosamide (NLM) NLM-NCs co-loaded PLGA-PEG-PLGA thermosensitive hydrogel |
|Intratumoral injection||PTX-NCs were prepared by the “3PNET” method||The new formula was compared to PTX-NCs, PTX-NCs-Ts Gel, NLM-NCs, NLM-NCs-Ts gel, and PN–NCs-Ts gel |
In vitro drug release
Cell culture models: MDA-MB-231 cells
In vivo model: BALB/c nude mice inoculated with MDA-MB-231 cells
|Sustained and significantly delayed drug release both in vitro and in vivo. |
The combination with NLM improved PTX cellular uptake, apoptosis, and provided inhibition of cell migration.
The in vivo studies showed significant inhibition of tumor growth with acceptable safety and effectively overcoming it. Triple-negative breast cancer (TNBC) progress and drastically prevented breast cancer stem cells (BCSCs).
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Haddad, R.; Alrabadi, N.; Altaani, B.; Li, T. Paclitaxel Drug Delivery Systems: Focus on Nanocrystals’ Surface Modifications. Polymers 2022, 14, 658. https://doi.org/10.3390/polym14040658
Haddad R, Alrabadi N, Altaani B, Li T. Paclitaxel Drug Delivery Systems: Focus on Nanocrystals’ Surface Modifications. Polymers. 2022; 14(4):658. https://doi.org/10.3390/polym14040658Chicago/Turabian Style
Haddad, Razan, Nasr Alrabadi, Bashar Altaani, and Tonglei Li. 2022. "Paclitaxel Drug Delivery Systems: Focus on Nanocrystals’ Surface Modifications" Polymers 14, no. 4: 658. https://doi.org/10.3390/polym14040658