Preparation and characterization of paclitaxel palmitate albumin nanoparticles with high loading efficacy: an in vitro and in vivo anti-tumor study in mouse models.

BACKGROUND: Combination of the prodrug technique with an albumin nano drug-loaded system is a novel promising approach for cancer treatment. However, the long-lasting and far-reaching challenge for the treatment of cancers lies in how to construct the albumin nanometer drug delivery system with lead compounds and their derivatives. METHODS: In this study, we reported the preparation of injectable albumin nanoparticles (NPs) with a high and quantitative drug loading system based on the NabTM technology of paclitaxel palmitate (PTX-PA). RESULTS: Our experimental study on drug tissue distribution in vivo demonstrated that the paclitaxel palmitate albumin nanoparticles (Nab-PTX-PA) remained in the tumor for a longer time post-injection. Compared with saline and paclitaxel albumin nanoparticles (Abraxane®), intravenous injection of Nab-PTX-PA not only reduced the toxicity of the drug in normal organs, and increased the body weight of the animals but maintained sustained release of paclitaxel (PTX) in the tumor, thereby displaying an excellent antitumor activity. Blood routine analysis showed that Nab-PTX-PA had fewer adverse effects or less toxicity to the normal organs, and it inhibited tumor cell proliferation more effectively as compared with commercial paclitaxel albumin nanoparticles. CONCLUSIONS: This carrier strategy for small molecule drugs is based on naturally evolved interactions between long-chain fatty acids (LCFAs) and Human Serum Albumin (HSA), demonstrated here for PTX. Nab-PTX-PA shows higher antitumor efficacy in vivo in breast cancer models. On the whole, this novel injectable Nab-PTX-PA has great potential as an effective drug delivery system in the treatment of breast cancer.

Model-based analysis of treatment effects of paclitaxel microspheres in a microscopic peritoneal carcinomatosis model in mice.

PURPOSE: Paclitaxel (PTX)-loaded genipin-crosslinked gelatin microspheres (GP-MS) are a prolonged IP delivery system under development for the treatment of peritoneal minimal residual disease (pMRD). Here, we show the use of a pharmacokinetic-pharmacodynamic (PKPD) modelling approach to inform the formulation development of PTX-GP-MS in a mice pMRD model. METHODS: PTX blood concentrations and survival data were obtained in Balb/c Nu mice receiving different single IP doses (7.5 and/or 35 mg/kg) of PTX-ethanolic loaded GP-MS (PTXEtOH-GP-MS), PTX-nanosuspension loaded GP-MS (PTXnano-GP-MS), and immediate release formulation Abraxane®. A population PK model was developed to characterize the PTX blood concentration pattern and to predict PTX concentrations in peritoneum. Afterwards, PKPD relationships between the predicted peritoneal or blood concentrations and survival were explored using time-to-event modelling. RESULTS: A PKPD model was developed that simultaneously describes the competing effects of treatment efficacy (driven by peritoneal concentration) and toxicity (driven by blood concentration) of PTX on survival. Clear survival advantages of PTXnano-GP-MS over PTXEtOH-GP-MS and Abraxane® were found. Simulations of different doses of PTXnano-GP-MS demonstrated that drug-induced toxicity is high at doses between 20 and 35 mg/kg. CONCLUSIONS: The model predicts that the dose range of 7.5-15 mg/kg of PTXnano-GP-MS provides an optimal balance between efficacy and safety.

Bioequivalence of paclitaxel protein-bound particles in patients with breast cancer: determining total and unbound paclitaxel in plasma by rapid equilibrium dialysis and liquid chromatography-tandem mass spectrometry.

Background and objective: Paclitaxel protein-bound particles for injectable suspension (nab-paclitaxel) showed many advantages in safety, effectiveness, and convenience. Different from conventional formulations, the bioequivalence evaluation of nab-paclitaxel formulations requires to determine the total amount of paclitaxel in plasma and the unbound paclitaxel to reflect their in vivo disposition. This study aimed to develop an analytical method to quantify the total and unbound paclitaxel in plasma and evaluate the bioequivalence of two formulations of nab-paclitaxel in patients with breast cancer. Materials and methods: An open-label, randomized, two-period crossover study was completed among 24 Chinese patients with breast cancer. The patients were randomized to receive either the test formulation on cycle 1 day 1 and after 21 days in cycle 2 day 1 by the reference formulation (Abraxane®), or vice versa. Rapid equilibrium dialysis was adopted to separate the unbound paclitaxel in human plasma. Total and unbound paclitaxel concentrations were measured by the validated liquid chromatography-tandem mass spectrometry methods over the range of 5.00-15,000 and 0.200-200 ng/mL, respectively. The bioequivalence of the test formulation to the reference formulation was assessed using the Food and Drug Administration and European Medicines Agency guidelines. Results: All the 90% confidence intervals (CIs) of the geometric mean ratios fell within the predetermined acceptance range. The 90% CIs for the area under the concentration-time curve (AUC) from 0 h to 72 h (AUC0-t), AUC from time zero to infinity (AUC0-∞), and peak plasma concentrations (Cmax) for total paclitaxel were 92.03%-98.05%, 91.98%-99.37%, and 91.37%-99.36%, respectively. The 90% CIs of AUC0-t, AUC0-∞, and Cmax for unbound paclitaxel were 86.77%-97.88%, 86.81%-97.88%, and 87.70%-98.86%, respectively. Conclusion: Bioequivalence between the two nab-paclitaxel formulations was confirmed for total and unbound paclitaxel at the studied dose regimen.

Drug Carrier-Oriented Polygeline for Preparing Novel Polygeline-Bound Paclitaxel Nanoparticles.

Polygeline is a highly promising drug carrier-oriented material for important applications in pharmacy field due to its low-cost and unique properties similar to albumin. In this study, polygeline-bound paclitaxel nanoparticles (Npb-PTXS) were fabricated through a combination of low-pressure emulsification and high-pressure homogenization. The effects of a series of production parameters on mean particle size, particle size distribution and drug loading of Npb-PTXS were systematically evaluated. The characteristics of Npb-PTXS, such as surface morphology, physical status of paclitaxel (PTX) in Npb-PTXS, redispersibility of Npb-PTXS in purified water and bioavailability in vivo were also investigated. It is revealed that the optimal preparation conditions included an aqueous phase pH value of about 6.5, protein mass concentration of 0.33%, with mass ratio of PTX to protein of 30%, high pressure of 1200 bar, high-pressure passes of 25 times and low-pressure emulsifying passes of 20 times. Obtained Npb-PTXS shows good resolubility compared to commercially available Abraxane®, containing round or oval shaped particles with mean particle size of around 188.3 nm, polydispersity index of 0.163 and zeta potential of -31.1 mV. PTX in Npb-PTX is amorphous, and its content is approximately 12.04%. Encapsulation efficiency of Npb-PTXS reaches 81.2%. Moreover, in vivo pharmacokinetic studies showed that the intravenous relative bioavailability of Npb-PTXS to Abraxane was 83.89%.

A Comparative In Vivo Study of Albumin-Coated Paclitaxel Nanocrystals and Abraxane.

Nanoparticulate drug carriers exploit the enhanced permeability of tumor vasculature to achieve selective delivery of chemotherapeutic drugs. For this purpose, nanoparticles (NPs) need to circulate with a long half-life, enter tumors via the permeable vasculature and stay in tumors via favorable interactions with tumor cells. To fulfill these requirements, albumin-coated nanocrystal formulation of paclitaxel (PTX), Cim-F-alb, featuring high drug loading content, physical stability in serum, and surface-bound albumin in its native conformation is prepared. The pharmacokinetic and biodistribution (PK/BD) profiles of Cim-F-alb in a mouse model of B16F10 melanoma show that Cim-F-alb exhibits a longer plasma half-life and a greater PTX deposition in tumors than Abraxane by ≈1.5 and ≈4.6 fold, respectively. Biolayer interferometry analysis indicates that Cim-F-alb has less interaction with serum proteins than nanocrystals lacking albumin coating, indicating the protective effect of the surface-bound albumin against opsonization in the initial deposition phase. With the advantageous PK/BD profiles, Cim-F-alb shows greater and longer-lasting anticancer efficacy than Abraxane at the equivalent dose. This study demonstrates the significance of controlling circulation stability and surface property of NPs in efficient drug delivery to tumors and enhanced anticancer efficacy.

Pharmacokinetics and safety of paclitaxel delivery into porcine airway walls by a new endobronchial drug delivery catheter.

BACKGROUND AND OBJECTIVE: Intratumoral administration of chemotherapeutic agents is a treatment modality that has proven efficacious in reducing the recurrence of tumours and increases specificity of treatment while minimizing systemic side effects. Direct intratumoral injection of malignant airway obstruction has potential therapeutic benefits but tissue drug concentrations and side-effect profiles are poorly understood. METHODS: Bronchial wall injection of generic paclitaxel (PTX) (102 injections of 0.05, 0.5, 1.5 or 2.5 mg/mL in 10 healthy pigs), saline (14 injections in 2 healthy pigs) or Abraxane (ABX) (24 injections of 0.5 mg/mL in 4 healthy pigs) was performed with a microneedle infusion catheter. Local histopathology, plasma and tissue PTX concentrations were evaluated at 7, 20 or 28 days post-injection. RESULTS: Injection of generic PTX directly into the bronchial wall at doses up to 1.5 mg/mL only caused minimal tissue injury. Dose-limiting tissue reaction was observed at 2.5 mg/mL. Plasma PTX was detectable for up to 5 days but not at 28 days, with area under the curve (AUC)(0-5d) 20- to 50-fold lower than the AUC(0-∞) of 6300 ng h/mL for the approved intravenous dose. At 7 and 28 days post-injection, bronchial PTX tissue concentrations were above a 10-nmol/L cancer therapeutic level. PTX was not found in peripheral tissues. Similar results were observed between ABX and generic PTX. CONCLUSION: Results of these studies confirm the administration of PTX directly into the bronchial wall is safe and feasible. PTX was detectable in plasma for <7 days but tissue concentrations remained therapeutic throughout the follow-up period.

Improved anticancer effects of albumin-bound paclitaxel nanoparticle via augmentation of EPR effect and albumin-protein interactions using S-nitrosated human serum albumin dimer.

In the latest trend of anticancer chemotherapy research, there were many macromolecular anticancer drugs developed based on enhanced permeability and retention (EPR) effect, such as albumin bound paclitaxel nanoparticle (nab- PTX, also called Abraxane®). However, cancers with low vascular permeability posed a challenge for these EPR based therapeutic systems. Augmenting the intrinsic EPR effect with an intrinsic vascular modulator such as nitric oxide (NO) could be a promising strategy. S-nitrosated human serum albumin dimer (SNO-HSA Dimer) shown promising activity previously was evaluated for the synergistic effect when used as a pretreatment agent in nab-PTX therapy against various tumor models. In the high vascular permeability C26 murine colon cancer subcutaneous inoculation model, SNO-HSA Dimer enhanced tumor selectivity of nab-PTX, and attenuated myelosuppression. SNO-HSA Dimer also augmented the tumor growth inhibition of nab-PTX in low vascular permeability B16 murine melanoma subcutaneous inoculation model. Furthermore, nab-PTX therapy combined with SNO-HSA Dimer showed higher antitumor activity and improved survival rate of SUIT2 human pancreatic cancer orthotopic model. In conclusion, SNO-HSA Dimer could enhance the therapeutic effect of nab-PTX even in low vascular permeability or intractable pancreatic cancers. The possible underlying mechanisms of action of SNO-HSA Dimer were discussed.

Biodegradable double-targeted PTX-mPEG-PLGA nanoparticles for ultrasound contrast enhanced imaging and antitumor therapy in vitro.

A porous-structure nano-scale ultrasound contrast agent (UCA) was made of monomethoxypoly (ethylene glycol)-poly (lactic-co-glycolic acid) (mPEG-PLGA), and modified by double-targeted antibody: anti-carcinoembryonic antigen (CEA) and anti-carbohydrate antigen 19-9 (CA19-9), as a double-targeted nanoparticles (NPs). Anti-tumor drug paclitaxel (PTX) was encapsulated in the double-targeted nanoparticles (NPs). The morphor and release curve were characterized. We verified a certain anticancer effect of PTX-NPs through cytotoxicity experiments. The cell uptake result showed much more NPs may be facilitated to ingress the cells or tissues with ultrasound (US) or ultrasound targeted microbubble destruction (UTMD) transient sonoporation in vitro. Ultrasound contrast-enhanced images in vitro and in vivo were investigated. Compared with SonoVue, the NPs prolonged imaging time in rabbit kidneys and tumor of nude mice, which make it possible to further enhance anti-tumor effects by extending retention time in the tumor region. The novel double-targeted NPs with the function of ultrasound contrast enhanced imaging and anti-tumor therapy can be a promising way in clinic.

Paclitaxel-Loaded TPGS-b-PCL Nanoparticles: In Vitro Cytotoxicity and Cellular Uptake in MCF-7 and MDA-MB-231 Cells versus mPEG-b-PCL Nanoparticles and Abraxane®.

Nanomedicines have become an attractive platform for the development of novel drug delivery systems in cancer chemotherapy. Polymeric nanoparticles (NPs) represent one of the best well-investigated nanosized carriers for delivery of antineoplastic compounds. The "Pegylation strategy" of drug delivery systems has been used in order to improve carrier biodistribution, however, some nanosized systems with PEG on their surface have exhibited poorly-cellular drug internalization. In this context, the purpose of the present study was to compare in vitro performance of two paclitaxel (PTX)-loaded NPs systems based on two biocompatible copolymers of alpha tocopheryl polyethylene glycol 1000 succinate-block-poly(ε-caprolactone) (TPGS-b-PCL) and methoxyPEG- block-poly(ε-caprolactone) (mPEG-b-PCL) in terms of citotoxicity and PTX cellular uptake. Fur- thermore, TPGS-b-PCL NPs were also copared with the commercially available PTX nano-sized formulation Abraxane®. Both TPGS-b-PCL and mPEG-b-PCL derivates were synthesized by ring opening polymerization of ε-caprolactone employing microwaved radiation. NPs were obtained by a solvent evaporation technique where the PTX content was determined by reverse-phase HPLC. The resulting NPs had an average size between 200 and 300 nm with a narrow size distribution. Also both NPs systems showed a spherical shape. The in vitro PTX release profile from the NPs was characterized employing the dialysis membrane method where all drug-loaded formulations showed a sustained and slow release of PTX. Finally, in vitro assays demonstrated that PTX-loaded TPGS- b-PCL exhibited a significant higher antitumor activity than PTX-loaded mPEG-b-PCL NPs and Abraxane® against an estrogen-dependent (MCF-7) and an estrogen independent (MDA-MB-231) breast cancer cells lines. Furthermore TPGS-b-PCL NPs showed a significant increase on PTX cellular uptake, for both breast cell lines, in comparison with mPEG-b-PCL NPs and Abraxane®. Overall findings confirmed that NPs based on TPGS-b-PCL as biomaterial demonstrated a better in vitro performance than NPs with PEG, representing an attractive alternative for the development of novel nanosized carriers for anticancer therapy.

Increased fibrosis and impaired intratumoral accumulation of macromolecules in a murine model of pancreatic cancer co-administered with FGF-2.

Pancreatic cancer is notorious for its poor prognosis. The histopathologic characteristic of pancreatic ductal adenocarcinoma (PDAC), which is the most common type of pancreatic cancer, is fibrosis within tumor tissue. Although fibrosis within tumor tissue is thought to impede drug therapy by interfering with the intratumoral accumulation of anti-tumor drugs, this hypothesis has yet to be proven directly in preclinical models. Here, we evaluated the effect of enhanced fibrosis on intratumoral accumulation of macromolecular drugs by increasing fibrosis in a murine tumor model of subcutaneously xenografted BxPC-3, a human PDAC cell line. When fibroblast growth factor-2 (FGF-2) was co-administered upon BxPC-3 inoculation, stromal fibrotic area was increased and was characterized by augmented murine collagen accumulation compared to inoculation of BxPC-3 alone, which correlated with increased monocyte/macrophage contents in the tumor tissues. We further discovered that the intratumoral accumulation of intravenously administrated fluorescein isothiocyanate-dextran of 2,000,000Da (2MDa) was significantly reduced in the FGF-2 co-administered tumors despite unaltered hyaluronan accumulation and pericyte coverage of the tumor neovasculature and increased lymphangiogenesis. Finally, we found that FGF-2 co-administered tumors are more refractory to macromolecular drug therapy using nab-paclitaxel (Abraxane). The model established and analyzed in this study, characterized by increased fibrotic component, provides a preclinical animal model suited to predict the intratumoral accumulation of macromolecular drugs and to evaluate the efficacy of drugs targeting the tumor stroma.

Albumin-Bound Paclitaxel: A Review in Non-Small Cell Lung Cancer.

Nanoparticle albumin-bound paclitaxel (Abraxane) [hereafter referred to as nab-paclitaxel] is a taxane developed to avoid some of the toxicities associated with solvent-bound (sb) paclitaxel. Nab-paclitaxel, in combination with carboplatin, is indicated for the first-line treatment of non-small cell lung cancer (NSCLC) in patients who are not candidates for curative surgery and/or radiation therapy. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of nab-paclitaxel in this indication. Compared with sb-paclitaxel plus carboplatin, nab-paclitaxel plus carboplatin significantly improved the objective response rate (ORR), but did not prolong progression-free survival or overall survival (OS), in the overall population of patients with advanced NSCLC in a multinational phase III trial. The nab-paclitaxel regimen also provided benefit over the sb-paclitaxel regimen in certain patient subgroups, including patients with squamous cell histology (in terms of ORR) and patients who were elderly (in terms of OS). Nab-paclitaxel plus carboplatin had a manageable tolerability profile with some benefits over sb-paclitaxel plus carboplatin, including lower rates of grade ≥3 neutropenia, peripheral neuropathy, arthralgia and myalgia, although was associated with more grade ≥3 anaemia and thrombocytopenia. Given its efficacy and tolerability, intravenous nab-paclitaxel plus carboplatin is a valuable first-line treatment option for patients with advanced NSCLC.