Table 1.

Modified PTX NC formulations for intravenous (IV) drug delivery.

PTX NC	Method of Preparation	The Models Used and the Reference or Control Formula	Benefits, Aims, and Other Notes	Refs.
Albumin-coated PTX-NC (Alb-PTX NCs)	NC crystallized in the medium containing Pluronic F-127 and then coated with albumin “Cim-F-alb”	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 Equivalent cytotoxicity. 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.	[160,161]
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.	[162]
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.	[163]
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.	[164]
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.	[165]
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.	[166]
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.	[167]
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 (PTX-NBD@PC-PEG NSs) Cell culture models: HeLa cells	The cube-shaped PTX-NBD@PC-PEG 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.	[168]
Surface-modified PTX with positively charged poly(allylamine hydrochloride) (PAH)	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.	[169]
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.	[158]
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.	[170]
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.	[171]
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.	[172]
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.	[173]
Platelet membrane-coated or cloaked PEG-PTX NCs (PPNCs)	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.	[174]
RGD peptide -PEGylated PTX NCs coated by polydopamine (PDA) (NC@PDA-PEG-RGD)	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.	[175]
PTX and lapatinib (LAPA) composite nanocrystals with PDA and PEG modification(cNC@PDA-PEG)	PEG coat was introduced into the cNC via PDA) coat to get PEGylated composite NCs (cNC@PDA-PEG). 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	cNC@PDA-PEG had optimum size and stability. The in vitro release study showed that both PTX and LAPA were released completely from cNC@PDA-PEG 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.	[176]