Paclitaxel Micelles Research Articles

Polycaprolactone-Vitamin E TPGS Micellar Formulation for Oral Delivery of Paclitaxel.

This study aimed to investigate the potential of polycaprolactone-vitamin E TPGS (PCL-TPGS) micelles as a delivery system for oral administration of paclitaxel (PTX). The PCL-TPGS copolymer was synthesized using ring opening polymerization, and PTX-loaded PCL-TPGS micelles (PTX micelles) were prepared via a co-solvent evaporation method. Characterization of these micelles included measurements of size, polydispersity, and encapsulation efficiency. The cellular uptake of PTX micelles was evaluated in Caco-2 cells using rhodamine 123 (Rh123) as a fluorescent probe. Moreover, an everted rat sac study was conducted to evaluate the ex vivo permeability of PTX micelles. Additionally, a comparative pharmacokinetic study of PTX micelles versus the marketed formulation, Ebetaxel® (a Taxol generic), was performed after a single oral administration to rats. The results demonstrated that the micellar formulation significantly improved PTX solubility (nearly 1 mg/mL). The in vitro stability and release of PTX micelles in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) demonstrated that PTX micelles remained stable for up to 24 h and significantly slowed the release of PTX in both media compared to Ebetaxel®. The in vitro cellular uptake, ex vivo intestinal permeability, and in vivo pharmacokinetic profile demonstrated that PTX micelles enhanced the permeability and facilitated a rapid absorption of the drug. Conclusively, the PCL7000-TPGS3500 micelles exhibit potential as an effective oral delivery system for PTX.

Dual Stimuli-Responsive Micelles for Imaging-Guided Mitochondrion-Targeted Photothermal/Photodynamic/Chemo Combination Therapy-Induced Immunogenic Cell Death.

As the special modality of cell death, immunogenic cell death (ICD) could activate immune response. Phototherapy in combination with chemotherapy (CT) is a particularly efficient tumor ICD inducing method that could overcome the defects of monotherapies. In this study, new dual stimuli-responsive micelles were designed and prepared for imaging-guided mitochondrion-targeted photothermal/photodynamic/CT combination therapy through inducing ICD. A dual-sensitive methoxy-polyethylene glycol-SS-poly(L-γ-glutamylglutamine)-SS-IR780 (mPEG-SS-PGG-SS-IR780) polymer was synthesized by grafting IR780 with biodegradable di-carboxyl PGG as the backbone, and mPEG-SS-PGG-SS-IR780/paclitaxel micelles (mPEG-SS-PGG-SS-IR780/PTXL MCs) were synthesized by encapsulating PTXL in the hydrophobic core. In-vivo and -vitro results demonstrated that the three-mode combination micelles inhibited tumor growth and enhanced the therapeutic efficacy of immunotherapy. The dual stimuli-responsive mPEG-SS-PGG-SS-IR780/PTXL MCs were able to facilitate tumor cell endocytosis of nanoparticles. They were also capable of promoting micelles disintegration and accelerating PTXL release. The mPEG-SS-PGG-SS-IR780/PTXL MCs induced mitochondrial dysfunction by directly targeting the mitochondria, considering the thermo- and reactive oxygen species (ROS) sensitivity of the mitochondria. Furthermore, the mPEG-SS-PGG-SS-IR780/PTXL MCs could play the diagnostic and therapeutic roles via imaging capabilities. In summary, this study formulated a high-efficiency nanoscale platform with great potential in combined therapy for tumors through ICD.

Efficacy and safety of polymeric micelle paclitaxel (pm-Pac) plus tislelizumab and carboplatin for first-line treatment of patients with advanced squamous non-small-cell lung cancer.

9036 Background: The pm-paclitaxel formulation for injection (pm-Pac), a novel drug delivery system composed of nanoparticle-encapsulated paclitaxel micelles, combined with cisplatin has been proven to improve clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC). But the efficacy and safety of pm-Pac in addition to PD-1/PD-L1 inhibitors had never been reported before. Methods: Treatment-naive, stage IIIB/IV Sq-NSCLC patients with ECOG PS 0-2(≤1, 91.1%) were eligible. Participants were given intravenous Tislelizumab (200mg, d1) plus pm-Pac (230 mg/m2, d1) and carboplatin (AUC 5, d1), every 3 weeks until progression or unacceptable toxicity, with local radiotherapy or surgery allowed if treatment needed. The primary endpoints were ORR and safety. The secondary endpoints include DCR, PFS, and OS. AEs were graded according to CTCAE v5.0. Results: From Nov 2021 to Dec 2022, 45 patients were enrolled. The median age was 68 years (range 41-84), and most were male (93%) and former/current smokers (87%). 3 patients had baseline brain metastases and 31 patients had baseline PD-L1 evaluated. Twenty-two patients (48.9%) received subsequent local treatment because of the stable efficacy, including 18 radiotherapy and 4 surgery. Among all, 2 achieved confirmed CR, 36 achieved PR, 7 achieved SD, ORR was 84.4% and DCR was 100%. PFS and OS were immature. Kaplan-Meier survival analysis indicated that the 6m-PFS rate was 94.8% (95%CI:89.8%，97.6%), and a total of 41 (91.1%) patients are still alive on 1L treatment at the last follow-up on Feb 2023.The most common TRAE were alopecia (91.1%), leukopenia (80%), peripheral neurosensory numbness (55.6%) and extremity pain (24.4%). The most common grade 3 or higher AE was neutropenia (33.3%), which is commonly associated with chemotherapy. Conclusions: This is the first report about the new chemo-drug pm-Pac plus PD-1 inhibitor regimen that significantly improved ORR for advanced Sq-NSCLC with a tolerable safety profile, supporting further development of this new combination in the first-line treatment. Response rates. [Table: see text]

Synergistic Encapsulation of Paclitaxel and Sorafenib by Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles for Ovarian Cancer Therapy.

Ovarian cancer has a high mortality rate due to difficult detection at an early stage. It is necessary to develop a novel anticancer treatment that demonstrates improved efficacy while reducing toxicity. Here, using the freeze-drying method, micelles encapsulating paclitaxel (PTX) and sorafenib (SRF) with various polymers were prepared, and the optimal polymer (mPEG-b-PCL) was selected by measuring drug loading (%), encapsulation efficiency (%), particle size, polydispersity index, and zeta potential. The final formulation was selected based on a molar ratio (PTX:SRF = 1:2.3) with synergistic effects on two ovarian cancer cell lines (SKOV3-red-fluc, HeyA8). In the in vitro release assay, PTX/SRF micelles showed a slower release than PTX and SRF single micelles. In pharmacokinetic evaluation, PTX/SRF micelles showed improved bioavailability compared to PTX/SRF solution. In in vivo toxicity assays, no significant differences were observed in body weight between the micellar formulation and the control group. The anticancer effect of PTX/SRF combination therapy was improved compared to the use of a single drug. In the xenografted BALB/c mouse model, the tumor growth inhibition rate of PTX/SRF micelles was 90.44%. Accordingly, PTX/SRF micelles showed improved anticancer effects compared to single-drug therapy in ovarian cancer (SKOV3-red-fluc).

A compound formulation of EGF-modified paclitaxel micelles and EGF-modified emodin micelles enhance the therapeutic effect of ovarian cancer

Ovarian cancer is a serious threat to female health, although the incidence of it is relatively low, its mortality rate remains high due to its intense invasion and metastasis. Therefore, it is urgent to explore new treatment strategies for ovarian cancer. In this study, paclitaxel and emodin were encapsulated in different micelles, and loaded on the surface of the micelles with epidermal growth factor (EGF) as the targeting molecule, made compound formulations in proportion. In this study, EGF-modified paclitaxel micelles and EGF-modified emodin micelles were characterized, their inhibitory effects on SKOV3 cell proliferation and invasion were studied in vivo and in vitro, and its targeting ability was confirmed. The results showed that the shape, particle size, zeta potential, release rate, encapsulation rate, polydispersity index, and other physical and chemical properties of EGF-modified paclitaxel micelles plus EGF-modified emodin micelles meet the requirements, and the modification of EGF on the micelle surface could obviously improve the uptake of SKOV3 cells and inhibit the proliferation of SKOV3 cells. The compound formulation can inhibit the invasion and metastasis of ovarian cancer by inhibiting the expression of hypoxia inducible factor-α, MMP-2, MMP-9, and VE-cadherin. The in vivo studies have also showed significant pharmacodynamics results. These results indicated that EGF-modified paclitaxel micelles plus EGF-modified emodin micelles provide a new strategy for the treatment of ovarian cancer.

Study on the preparation and activity of intelligent response poly(lactic-co-glycolic acid)-ss-polyethylene glycol copolymer micelles.

Amphiphilic polymer micellar carriers are the most commonly used nanocarriers for oral delivery of hydrophobic drugs because their hydrophilic shell can avoid the recognition of the reticuloendothelial system (RES), has excellent drug-carrying capacity, and protect the drug from inactivation in the gastrointestinal fluid. The polymer micelle shell can enter cancer cells by endocytosis, and autophagy in cells, degradation by lysosomal pathway, so as to release drugs, prolong the circulation time of drugs in vivo, and then achieve the effect of drug sustained release. In this study, the glutathione-responsive PLGA-ss-PEG loaded paclitaxel (PTX) micelles (PLGA-ss-PEG-PTX) were developed for anticancer therapy. With its long-term circulation and EPR (enhanced permeability and retention) effect, and the micelle had disulfide bond, which could be used as the recognition group of tumor microenvironment, so that the PLGA-ss-PEG-PTX could specifically accumulate at the tumor site, so as to produce better anti-tumor effect. The PLGA-ss-PEG-PTX was formulated by the emulsification method in this study. The drug loading was about 21.54%, the entrapment efficiency was about 94.2%, and the particle size range was about 90nm with narrow particle size distribution. Cytotoxicity and embryonic toxicity experiments were carried out using mouse lung cancer cells (LLC) and zebrafish fertilized eggs. It was proved that the low concentration of blank micelles had little cytotoxicity, but high concentration of blank micelles had adverse effects on zebrafish embryonic development, resulting in embryonic malformation. The uptake of drugs by cancer cells was studied by a high connotation cell imaging analysis system. The experiments showed that the drug molecules encapsulated in micelles could achieve higher uptake by cells compared with free drug molecules. In addition, in the in vivo evaluation experiment of drugs, the PLGA-ss-PEG-PTX could significantly enhance the therapeutic effect of the PTX, improve its water solubility, and improve its oral bioavailability.

A multistage oral delivery system of PTX for improving oral bioavailability and enhancing anticancer efficacy

Objective Bromotetrandrine (W198) was reported as a P-glycoprotein (P-gp) inhibitor. We aimed to prepare oral W198 micelles following by paclitaxel (PTX) micelles (W198/PTX micelles) to improve the clinical application of PTX. Significance The poor water solubility, intestinal permeability, and multidrug resistance (MDR) of PTX can be improved in the multistage oral delivery system. Methods The novel W198/PTX oral micelles were developed by water-bath ultrasound method and were evaluated in vivo and in vitro in 4T1 orthotopic tumor-bearing mice model. Results PTX micelles and W198 micelles were prepared to be round and uniform. W198 micelles pre-administrated group showed higher cellular uptake efficiency of PTX on Caco-2 cells and more prominent cytotoxicity compared with W198-untreated group on 4T1 cells. The oral bioavailability of W198/PTX micelles group was nearly 5.7-folds higher than the PTX micelles only group. In addition, W198/PTX micelles showed enhanced anticancer efficacy. Conclusions We established a multistage oral delivery system to improve oral bioavailability and anticancer efficacy of PTX.

Development of a size-tunable paclitaxel micelle using a microfluidic-based system and evaluation of its in-vitro efficacy and intracellular delivery

Many challenges still remain for the successful translation of nanodelivery systems from the discovery to clinical practice. The primary concerns include easy scale-up process, uniformity, low size variation, and the ability to control critical physicochemical properties, including size and shape. In the current study, we have developed an easy-to-scale, size-tunable polymeric micelle formulation of paclitaxel using Soluplus, an amphiphilic graft copolymer with the help of a microfluidic platform. Two variable-sized polymeric micelles, ~90 nm, and ~180 nm were prepared by the variation of the drug: polymer ratio. Physicochemical characterization of the micelles was performed in terms of size, polydispersity, solubility, solubility factor, drug loading, and drug release. In-vitro efficacy was analyzed in terms of cytotoxicity in both 2D and 3D spheroid models, along with penetration of the micelles in the 3D spheroid. Intracellular uptake and lysosomal colocalization were also studied. Results demonstrated that the smaller micelles have better encapsulation efficiency with controlled drug release and enhanced cytotoxicity in both 2D and 3D models. Cellular internalization studies indicated that the smaller micelles have higher cellular uptake. In the 3D spheroid model, the smaller micelles exhibited almost complete penetration in 24 h, whereas the larger micelles showed negligible penetration. Altogether, this study indicated that this process could be used for the development of clinically successful nanoformulations.

Mixed micelles of TPGS and Soluplus® for co-delivery of paclitaxel and fenretinide: in vitro and in vivo anticancer study

Fenretinide (4-HPR), as a semi-synthetic retinoid, has apoptosis-promoting effects as a single agent and chemotherapy synergist in vitro. When a human ovarian cancer cells line (A2780s) was treated with both PTX and 4-HPR, there was a synergistic anti-cancer effect demonstrated with a average combination index of 0.44. In this research, a new TPGS-Soluplus® mixed micelles were developed which encapsulation efficiencies of paclitaxel (PTX) and fenretinide (4-HPR) were as high as 98%, and the average diameter of the micelles was 66.26 nm. Cytotoxicity of the mixed micelles co-delivered with PTX and 4-HPR reduced significantly 7.3 and 25.1 times compared with free drug respectively in A2780s cells. More importantly, in vivo pharmacokinetic study, the loaded drugs in mixed micelles exhibited higher AUC and t1/2 values than free drugs. Furthermore, in vivo antitumor efficacy experiments demonstrated that PF-TS exhibited superior in vivo antitumor activity on the inhibition rate of tumor growth than other treatment groups (77.8% corresponding tumor growth inhibition in PF-TS treated group vs 19.9, 12.5, and 26.0% of tumor growth inhibition rate in Taxol®, 4-HPR, and Taxol®+4-HPR, respectively). Therefore, the mixed micelles of co-deliver PTX and 4-HPR successfully constructed may hopefully be applied to the cancer combination treatment with less toxic effect and more antitumor activity.

Multi-functional chitosan polymeric micelles as oral paclitaxel delivery systems for enhanced bioavailability and anti-tumor efficacy.

Chitosan is widely used as a permeation enhancer for oral drug delivery, although its drawbacks include a limited enhancement of drug bioavailability and an inability to form micelles. In this study, we designed a novel chitosan derivative (GA-CS-TPGS copolymer) and constructed paclitaxel micelles (PTX-Micelles) designed to have multiple functions associated with the GA-CS-TPGS copolymer (enhanced bioadhesion, inhibited P-gp efflux and drug metabolism in liver) and the micelles (enhanced solubility and permeability) to enhance the bioavailability and anti-tumor efficacy of PTX. The results showed that the PTX-Micelles system could alter the in vivo pharmacokinetic performance and therapeutic effect of PTX via its predesigned functions. The bioavailability of PTX was enhanced approximately 3.80-fold by the PTX-Micelles, and an enhanced anti-lung tumor efficacy of PTX-Micelles was observed when compared to Taxol®. The results of this study indicate that constructing micelles with a multifunctional chitosan derivative may be a promising approach to enhance the oral bioavailability and anti-tumor efficacy of poorly soluble drugs.

Targeting cancer cells with nanotherapeutics and nanodiagnostics: Current status and future perspectives.

Nanotechnology is reshaping health care strategies and is expected to exert a tremendous impact in the coming years offering better healthcare facilities. It has led to not only therapeutic drug delivery feasibility but also to diagnostics. Materials in the size of nano range (1-100 nm) used in the design, fabrication, regulation, and application of therapeutic drugs or devices are classified as medical nanotechnology and nanopharmacology. Delivery of more complex molecules to the specific site of action as well as gene therapy has pushed forward the nanoparticle-based drug delivery to its maximum. Areas that benefit from nano-based drug delivery systems are cancer, diabetes, infectious diseases, neurodegenerative diseases, blood disorders and orthopedic-related ailments. Moreover, development of nanotherapeutics with multi-functionalities has a considerable potential to fill the gaps that exist in the present therapeutic domain. In cancer treatment, nanomedicines have superiority over current therapeutic practices as they can effectively deliver the drug to the affected tissues, thus reducing drug toxicities. Along this line, polymeric conjugates of asparaginase and polymeric micelles of paclitaxel have recently been recommended for the treatment of various types of cancers. Nanotechnology-based therapeutics and diagnostics provide greater effectiveness with less or no toxicity concerns. Similarly, diagnostic imaging holds promising future applications with newer nano-level imaging elements. Advancements in nanotechnology have emerged to a newer direction which use nanorobotics for various applications in healthcare. Accordingly, this review comprehensively highlights the potentialities of various nanocarriers and nanomedicines for multifaceted applications in diagnostics and drug delivery, especially the potentialities of polymeric nanoparticle, nanoemulsion, solid-lipid nanoparticle, nanostructured lipid carrier, self-micellizing anticancer lipids, dendrimer, nanocapsule and nanosponge-based therapeutic approaches in the field of cancer. Furthermore, this article summarizes the most recent literature pertaining to the use of nano-technology in the field of medicine, particularly in treating cancer patients.

The enhanced treatment efficacy of invasive brain glioma by dual-targeted artemether plus paclitaxel micelles

High grade-gliomas are highly invasive and prone to metastasis, leading to poor survival and prognosis. Currently, we urgently need a new treatment strategy to effectively inhibit glioma. In this study, artemether and paclitaxel were used as two agents for tumour suppression. Two functional materials were synthesised and modified on the surface of the micelle as targeting molecules. The addition of two functional materials confers the ability of the micelles to effectively cross the blood-brain barrier (BBB) and then target the glioma cells. Thus, this dual-targeted delivery system allows the drug to play a better role in inhibiting tumour invasion and vasculogenic mimicry (VM) channels. In this paper, the anticancer effects of dual-targeted artemether plus paclitaxel micelles on glioma U87 cells were studied in three aspects: (I) In vitro and in vivo targeting assessment, including the role of penetrating BBB and targeting glioma; (II) In vitro regulation of invasion-associated proteins; (III) Inhibition of VM channels formation and invasion in vitro; (IV) The study of pharmacodynamics in tumour-bearing mice. These results suggest that dual-targeted artemether plus paclitaxel micelle may provide a new strategy to treat glioma via inhibiting invasive and VM channels.

Anisamide-functionalized pH-responsive amphiphilic chitosan-based paclitaxel micelles for sigma-1 receptor targeted prostate cancer treatment

Controlled release and tumor-selective distribution are highly desirable for anticancer nanomedicines. Here, we design and synthesize an anisamide-conjugated N-octyl-N,O-maleoyl-O-phosphoryl chitosan (a-OMPC) which can form amphiphilic micelles featuring pH-responsive release and high affinity to sigma-1 receptor-overexpressed tumors for paclitaxel (PTX) delivery. Thereinto, maleoyl and phosphoryl groups cooperatively contribute to pH-responsive drug release due to a conversion from hydrophile to hydrophobe in the acidic microenvironment of endo/lysosomes. We demonstrated that PTX-loaded a-OMPC micelles (PTX-aM) enhanced the cellular internalization via the affinity between anisamide and sigma-1 receptor, rapidly released drug in endo/lysosomes and elevated the cytotoxicity against PC-3 cells. The in vivo studies further verified that PTX-aM could largely accumulate at the tumor site even after 24 h of administration, resulting in obvious inhibition effect and prolonged survival period in PC-3 tumor xenograft-bearing mice. Moreover, OMPC showed no obvious hemolytic and acute toxicity. Collectively, this chitosan derivate holds a promising potential in application of prostate cancer-targeted drug delivery system.

Collagenase Nanoparticles Enhance the Penetration of Drugs into Pancreatic Tumors.

Overexpressed extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDAC) limits drug penetration into the tumor and is associated with poor prognosis. Here, we demonstrate that a pretreatment based on a proteolytic-enzyme nanoparticle system disassembles the dense PDAC collagen stroma and increases drug penetration into the pancreatic tumor. More specifically, the collagozome, a 100 nm liposome encapsulating collagenase, was rationally designed to protect the collagenase from premature deactivation and prolonged its release rate at the target site. Collagen is the main component of the PDAC stroma, reaching 12.8 ± 2.3% vol in diseased mice pancreases, compared to 1.4 ± 0.4% in healthy mice. Upon intravenous injection of the collagozome, ∼1% of the injected dose reached the pancreas over 8 h, reducing the level of fibrotic tissue to 5.6 ± 0.8%. The collagozome pretreatment allowed increased drug penetration into the pancreas and improved PDAC treatment. PDAC tumors, pretreated with the collagozome followed by paclitaxel micelles, were 87% smaller than tumors pretreated with empty liposomes followed by paclitaxel micelles. Interestingly, degrading the ECM did not increase the number of circulating tumor cells or metastasis. This strategy holds promise for degrading the extracellular stroma in other diseases as well, such as liver fibrosis, enhancing tissue permeability before drug administration.

Preparation and In-vitro Evaluation of Levan Micelles: A Polyfructan Based Nano-carrier for Breast Cancer Targeted Delivery

Background: Levans are biopolymers of fructose, produced by different microorganisms. Fructose present in the levan micelles binds with the Glucose Transporter 5 (GLUT 5) which is overexpressed in the breast cancer cells. Objective: Increased solubility of paclitaxel by loading in the GLUT 5 transporter targeted levan-based micelles may enhance its bioavailability and facilitate a targeted delivery to the breast cancer cells. Methods and Results: Critical micelle concentration of levan with an average molecular weight of 800,000 Dalton was found to be 0.125µM corresponding to 0.1mg/mL using pyrene I3/I1 method. At critical micelle concentration (CMC), levan formed very mono-disperse (PDI-0.082) micellar particles with a particle size of 153.1 ± 2.31nm and -14.6 ± 2mV zeta potential. In-vitro drug release study was performed to identify the fit kinetic model along with Fourier transform infrared analysis and Differential scanning calorimetry studies. In-vitro kinetic model fitting revealed first-order drug release from the prepared micellar composition. The drug-loaded micellar composition was studied for its anticancer activity in breast cancer cell line. The IC50 value obtained was 1.525 ± 0.11nM on MCF7 cell line. Conclusion: Paclitaxel micelles showed a nineteen-fold improvement in the IC50 value compared to free paclitaxel. Hemocompatibility study was performed with a view to parenteral administration. This solution containing drug was found to be hemocompatible when added to bovine blood in 1:4 ration. Micelles are proven fairly compatible on the basis of hemolysis test results.

Improving Drug Delivery of Micellar Paclitaxel against Non-Small Cell Lung Cancer by Coloading Itraconazole as a Micelle Stabilizer and a Tumor Vascular Manipulator.

Although polymeric micelles of paclitaxel (PTX) significantly reduce excipient-induced toxicity compared with Taxol, they exhibit few clinical advantages in tumor inhibition and overall survival. To improve, itraconazole (ITA), an antifungal drug with potent anti-angiogenesis activity, is co-encapsulated together with PTX within the PEG-PLA micelles. The strong intermolecular interactions between the payloads inhibit drug crystallization and prevent drugs from binding with external proteins, render super-stable micelles upon dilution and exposure to biological environment, and enter the tumor cells through endocytosis. The co-encapsulated micelles show strong anti-proliferation potency against non-small-cell lung cancer (NSCLC) and even PTX resistant NSCLC cells in vitro and significantly improve the drug accumulation within the tumor in vivo. Compared with PTX monotherapy or combination therapy using individual PTX and ITA micelles, the co-encapsulated micelle demonstrates strikingly superior efficacy in tumor growth inhibition, recurrence prevention, and reversion of PTX resistance, in Kras mutant patient derived xenografts, orthotropic models, and paclitaxel-resistance subcutaneous models. Besides the pharmacokinetic improvement, therapeutic benefits are also contributed by angiogenesis inhibition and blood vessel normalization by ITA. Utilizing the pharmaceutical and pharmacological synergies between the therapeutic agents, a simple yet effective design of a combination cancer nanomedicine that is industrially scalable and clinically translatable is achieved.

Functional paclitaxel plus honokiol micelles destroying tumour metastasis in treatment of non-small-cell lung cancer

Treatment effect of chemotherapy for aggressive non-small-cell lung cancer (NSCLC) is usually unsatisfactory for non-selective distributions of anticancer drugs, generation of vasculogenic mimicry (VM) channels, high metastasis and recurrence rate. Therefore, we developed a kind of dequalinium (DQA) modified paclitaxel plus honokiol micelles in this study to destroy VM channels and inhibit tumour metastasis. In vitro assays indicated that the targeting paclitaxel micelles with ideal physicochemical characteristics could exhibit not only the powerful cytotoxicity on Lewis lung tumour (LLT) cells but also the effective suppression on VM channels and tumour metastasis. Action mechanism studies manifested that DQA modified paclitaxel plus honokiol micelles could activate apoptotic enzymes caspase-3 and caspase-9 as well as down-regulate FAK, PI3K, MMP-2 and MMP-9. In vivo assays indicated that polymeric micelles could increase selective accumulation of chemotherapeutic drugs at tumour sites and showed a conspicuous antitumour efficacy. Hence, the DQA modified paclitaxel plus honokiol micelles prepared in this study provided a potential treatment strategy for NSCLC.

Abstract 4662: Comparing 2D and 3D culture models for in vitro therapeutic screening of paclitaxel loaded micelles co-administered with iRGD peptide

Abstract Clinical efficacy of paclitaxel, a potent chemotherapeutic agent, is limited by its nonspecificity that leads to toxic side effects. Polymeric micellar formulations of paclitaxel were designed with the long term goals of decreasing toxicity by tumor targeting, increasing circulation time, and enhancing permeability and retention in solid tumors. Biodegradable amphiphilic block copolymers that self assemble into micelles were used to entrap hydrophobic paclitaxel in the core. Traditional 2D cell culture models are standard for cytotoxicity assays. However, they lack the diffusion gradient and cell to cell interactions present in solid tumors which 3D multicellular tumor spheroids are capable of providing. We evaluated the in vitro cytotoxicity of polymeric micelles entrapping paclitaxel in 3D multicellular tumor spheroids of triple negative breast cancer cells and compared it with the standard 2D model. We added the cell penetrating iRGD peptide with the expectation that the iRGD peptide will increase the cellular uptake of the paclitaxel micelles. Particle uptake is enhanced due to the interaction of the iRGD peptide with the highly expressed integrin receptor on the cell surface, followed by neuropilin receptor binding which mediates an active transport system for deep tumor permeation. Paclitaxel loaded micelles were prepared and the drug content was analyzed. The cytotoxicity of the micellar paclitaxel nanocarrier system was studied in both the 2D and 3D cell culture models. Micellar paclitaxel induced cytotoxicity was significantly higher than free paclitaxel for the same concentrations of paclitaxel. Furthermore, a synergistic growth inhibitory response was observed upon coadministration of iRGD compared to treatment with the paclitaxel loaded nanocarriers on their own. Significantly higher concentration of the drug was needed in the 3D cultures to achieve comparable levels of cytotoxicity to the 2D cell culture models. This suggested that multicellular tumor spheroids exhibit higher resistance to anticancer drugs, supporting the fact that 3D culture is the better model to study in vitro cytotoxicity and likely to produce biorelevant data. Citation Format: Nayela N. Chowdhury, Nandita G. Das, Sudip K. Das. Comparing 2D and 3D culture models for in vitro therapeutic screening of paclitaxel loaded micelles co-administered with iRGD peptide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4662.

Multifunctional Hyaluronic Acid-Decorated Redox-Responsive Magnetic Complex Micelle for Targeted Drug Delivery with Enhanced Antitumor Efficiency and Anti-Cell-Migration Activity.

A novel multifunctional hyaluronic acid-decorated redox-responsive magnetic complex micelle (HA/CSO-SS-Hex/Fe3O4/PTX) based on a reducible hexadecanol-modified chitosan oligosaccharide polymer micelle (CSO-SS-Hex) coated with hyaluronic acid (HA) and loaded with paclitaxel (PTX) Fe3O4 nanoparticles is developed. HA is coated onto the surface of micelles via electrostatic absorption and acts as a targeting ligand for CD44 over expression in many tumor cells. A CSO-SS-Hex polymer micelle was used for PTX incorporation and GSH-triggered intracellular release. The PTX in micelles was used to provide chemotherapy. Fe3O4 nanoparticles were used for magnetic targeting. The complex micelle showed enhanced antitumor efficiency and anti-cell-migration activity. The HA/CSO-SS-Hex/Fe3O4/PTX micelle was stable under physiological conditions, while it was sensitive to release the loaded drug in the presence of 10 mM glutathione (GSH). The complex micelle showed enhanced cellular uptake and fast drug release due to the combined effect of magnet targeting, CD44 receptor-mediated internalization and redox-response drug release in tumor cells. Cell viability tests revealed that HA/CSO-SS-Hex/Fe3O4/PTX micelle displayed enhanced cytotoxicity against A549, B16F10 and HepG2 cell lines compared to non-targeted formulations of PTX. An anti-cell migration assay was also performed. The result showed that although there was no significant difference in the anti-cell migration activities between the HA/CSO-SS-Hex/Fe3O4/PTX micelle and free PTX, the activities of HA/CSO-SS-Hex/Fe3O4/PTX were stronger than non-targeted CSO-SS-Hex/Fe3O4/PTX micelles. Thus, the novel HA/CSO-SS-Hex/Fe3O4/PTX micelle is highly effective for targeted drug delivery and might have potential implications for the chemotherapy of primary tumors and their metastases.

A simple reduction-sensitive micelles co-delivery of paclitaxel and dasatinib to overcome tumor multidrug resistance.

Multidrug resistance (MDR) is one of the major obstacles in successful chemotherapy. The combination of chemotherapy drugs and multidrug-resistant reversing agents for treating MDR tumor is a good strategy to overcome MDR. In this work, we prepared the simple redox-responsive micelles based on mPEG-SS-C18 as a co-delivery system to load the paclitaxel (PTX) and dasatinib (DAS) for treatment of MCF-7/ADR cells. The co-loaded micelles had a good dispersity and a spherical shape with a uniform size distribution, and they could quickly disassemble and rapidly release drugs under the reduction environment. Compared with MCF-7 cells, the DAS and PTX co-loaded redox-sensitive micelle (SS-PDNPs) showed stronger cytotoxicity and a more improving intracellular drug concentration than other drug formulations in MCF-7/ADR cells. In summary, the results suggested that the simple co-delivery micelles of PTX and DAS possessed significant potential to overcome drug resistance in cancer therapy.