Paclitaxel Conjugate Research Articles

A Novel Paclitaxel Conjugate with Higher Efficiency and Lower Toxicity: A New Drug Candidate for Cancer Treatment.

Paclitaxel-lipoate (IDD-1040) is a conjugate formed by the chemical joining of the two compounds, by condensing a lipoic acid moiety to the C2′ of paclitaxel. IDD-1040 was evaluated for its anti-tumor activity and potential druggability, using an in vivo non-small-cell, lung cancer (NSCLC) xenograft mouse model. In the in vivo studies, IDD-1040 showed a maximum tolerated dose (MTD) of 250 mg/kg compared to paclitaxel (PTX), with an MTD of 20 mg/kg. Most interesting, IDD-1040 demonstrated higher anti-tumor activity, and its inhibitory activity on tumor volume (cell growth) was dose-dependent. That anti-tumor activity persisted for two weeks after cessation of IDD-1040 treatment, as opposed to PTX cessation, after which the tumor relapsed, confirming that IDD-1040 exhibits superior tumor inhibition. Similar to PTX treatment, no marked body weight decrease was observed during IDD-1040 treatment, indicating a low toxicity profile. The increase in animal body weight noted over time was due to the increasing weight of tumors, recorded in all the mouse test groups. The results also showed that mortality rate of mice was reduced by treatment with IDD-1040, more so than with PTX. Furthermore, in a preliminary study on the ex vivo distribution of IDD-1040, neutropenia was primarily concentrated in the liver 1 h after injection, and most of the drug was metabolized by the liver in 24 h. All of these results demonstrate IDD-1040’s great potential as a candidate drug for cancer treatment.

Enhancement mitochondrial apoptosis in breast cancer cells by paclitaxel-triphenylphosphonium conjugate in DNA aptamer modified nanoparticles

Mitochondria is a major regulator of inducing tumor apoptosis and it is as a prime target for chemotherapy. Anticancers need to access specific tumor cells and also pass through different barriers such as outer and inner membranes of mitochondria. Targeted accumulation of paclitaxel (PTX) within the mitochondria was achieved by direct conjugation of PTX with triphenylphosphonium (TPP) as a mitochondrial membrane-permeable cation. PTX-TPP prodrug was synthesized by pH-sensitive ester bond between the hydroxyl function of PTX and the carboxylic function of TPP. This ester bond is only cleaved by the mitochondrial aldehyde dehydrogenase. Prodrug was loaded in the albumin nanoparticles by nab-technology. The surface aptamer modification of nanoparticles was done by MUC1 DNA aptamer in order to targeting of tumor cells overexpressing MUC1. The yield of PTX-TPP conjugation was 81% and the particle size of final nanoparticles was 139 nm. The aptamer-modified nanoparticles significantly increased the cellular uptake to 99.9%, and demonstrated good mitochondrial uptake in the confocal fluorescence images leading to apoptosis of MCF-7 breast cancer cells. Early apoptosis and late apoptotic/necrotic phase of cells after 24 h were 26.4% and 25.3%, respectively, compared to 5.27% and 4.74% for free PTX. The targeted nanoparticles exhibited the superior in vitro anticancer efficacy of up to 17.8 fold higher than free PTX after 72 h. This multi-targeting strategy induced the mitochondrial apoptosis to killing tumor cells.

Synthesis and Evaluation of GnRHa-paclitaxel Tumor-targeting Conjugates†

Tumor targeting can be achieved by combining a chemotherapeutic agent with a targeting moiety,which recognizes tumor-specific or highly expressed receptors on cancer cells. GnRH receptor is over-expressed on various tumor cells but is barely expressed in healthy visceral organs which makes it possible to use GnRH analogues( GnRHa) as the targeting moieties to deliver cytotoxic agents. Two conjugates were synthesized by incorporating paclitaxel( PTX) into GnRH analogue which was synthesized in the solid phase,the conjugation of PTX with GnRH analogs was performed by thio-ether bond and disulfide bond as a linker. The purity of the conjugates was analyzed by high performance liquid chromatography( HPLC) and the structures of the conjugates were confirmed by high resolution mass spectrum( HRMS). The resulting conjugates 1 and 2both preserved the cytotoxic activity of PTX and also retained the high binding affinity of the peptide hormone portion of the conjugates. The high affinity indicated that the conjugates might be specifically delivered to tumor tissues or cells via endocytosis mediated by GnRH receptor. The results showed that more than 50%prototypes of conjugate 1 remained with incubating in human serum for 24 h which indicating a favorable stability.

A Simple Glutathione-Responsive Turn-On Theranostic Nanoparticle for Dual-Modal Imaging and Chemo-Photothermal Combination Therapy.

Constructing a tumor microenvironment stimuli activatable theranostic nanoparticle with simple components and preparation procedures for multimodality imaging and therapy remains a major challenge for current theranostic systems. Here we report a novel and simple glutathione (GSH)-responsive turn-on theranostic nanoparticle for dual-modal imaging and combination therapy. The theranostic nanoparticle, DHP, consisting of a disulfide-bond-linked hydroxyethyl starch paclitaxel conjugate (HES-SS-PTX) and a near-infrared (NIR) cyanine fluorophore DiR, is prepared with a simple one-step dialysis method. As DiR is encapsulated within the hydrophobic core formed by HES-SS-PTX, the fluorescence of DiR is quenched by the aggregation-caused quenching (ACQ) effect. Nonetheless, once DHP is internalized by cancer cells, the disulfide bond of HES-SS-PTX can be cleaved by intracellular GSH, leading to the synchronized release of conjugated PTX and loaded DiR. The released PTX could exert its therapeutic effect, while DiR could adsorb onto nearby endosome/lysosome membranes and regain its fluorescence. Thus, DHP could monitor the release and therapeutic effect of PTX through the fluorescence recovery of DiR. Remarkably, DHP can also be used as an in vivo probe for both fluorescent and photoacoustic imaging and at the same time achieves potent antitumor efficacy through chemo-photothermal combination therapy. This study provides novel insights into designing clinically translatable turn-on theranostic systems.

RGD peptide-decorated micelles assembled from polymer–paclitaxel conjugates towards gastric cancer therapy

Development of polymer-drug conjugate capable of controlled drug release is urgently needed for gastric cancer therapy. Herein, arginine-glycine-aspartic acid (RGD)-decorated polyethylene glycol (PEG)-paclitaxel (PTX) conjugates containing disulfide linkage were synthesized. The amphiphilic PEG-PTX conjugates were found to assemble into micelles (RGD@Micelles), which would be decomposed under the reduction of glutathione (GSH) and finally release PTX in weakly acidic conditions characteristic of intracellular environment. The RGD@Micelles were spherical nanoparticles with an average hydrodynamic size of ˜50 nm, which were stable in physiological environment. The release of PTX from the micelles in response to GSH was investigated. In vitro cell assay suggested that the RGD@Micelles could target the gastric cancer cells and inhibit cell proliferation by inducing apoptosis. In vivo experiments indicated that the RGD@Micelles could be delivered to the tumor site and inhibit the tumor growth efficiently by releasing PTX inside the tumor cells. This type of micelles exhibited high therapeutic efficacy and low side effects, providing new insights into targeted drug delivery for gastric cancer therapy.

Synthesis and Antiproliferative Activities of Conjugates of Paclitaxel and Camptothecin with a Cyclic Cell-Penetrating Peptide.

Cell-penetrating peptide [WR]5 has been previously shown to be an efficient molecular transporter for various hydrophilic and hydrophobic molecules. The peptide was synthesized using Fmoc/tBu solid-phase chemistry, and one arginine was replaced with one lysine to enable the conjugation with the anticancer drugs. Paclitaxel (PTX) was functionalized with an esterification reaction at the C2′ hydroxyl group of PTX with glutaric anhydride and conjugated with the cyclic peptide [W(WR)4K(βAla)] in DMF to obtain the peptide-drug conjugate PTX1. Furthermore, camptothecin (CPT) was modified at the C(20)-hydroxyl group through the reaction with triphosgene. Then, it was conjugated with two functionalized cyclic peptides through a formyl linker affording two different conjugates, namely CPT1 and CPT2. All the conjugates showed better water solubility as compared to the parent drug. The cytotoxicity assay of the drugs and their conjugates with the peptides were evaluated in the human breast cancer MCF-7 cell line. PTX inhibited cell proliferation by 39% while the PTX-peptide conjugate inhibited the proliferation by ~18% after 72 h incubation. On the other hand, CPT, CPT1, and CPT2 reduced the cell proliferation by 68%, 39%, and 62%, respectively, in the MCF-7 cell lines at 5 µM concentration after 72 h incubation.

Synthesis and anti-cancer evaluation of folic acid-peptide- paclitaxel conjugates for addressing drug resistance

The drug resistance and the poor water solubility are major limitations of paclitaxel (PTX) of based chemotherapy. To conquer the two problems, targeting folate (FA) receptor PTX-lytic peptides conjugates were synthesized and evaluated. Compared with PTX, FA-P3-PTX and FA-P7-PTX displayed significantly enhanced cell toxicity in many cancer cells, particularly drug resistant cancer cells MCF-7/PTX.FA-P7-PTX possessed stronger effect on cell toxicity (IC50 = 2.92 ± 0.2 μM), membrane disrupting activity and pro-apoptosis in MCF-7/PTX cells than FA-P3-PTX. Further investigation displayed that the anti-cancer mechanisms of FA-P3-PTX and FA-P7-PTX might be a mitochondrial impairment and caspase-3-dependent apoptotic cell death. Furthermore, the in vivo antitumor efficacy study confirmed that FA-P7-PTX performed more stronger potency in inhibition of tumors growth than PTX.The study demonstrated that conjugate FA-P7-PTX with superior properties for antineoplastic activity, which makes it a promising potential candidate for drug-resistant cancer therapy.

Preparation and anticancer activity evaluation of self-assembled paclitaxel conjugated MPEG-PCL micelles on 4T1 cells

In this study, we prepared self-assembled micelles with methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) (MPEG-PCL) for paclitaxel (PTX) delivery. MPEG-PCL was synthesized by ring-opening polymerization in which the hydroxyl group was substituted for a carboxyl group by succinic anhydride. PTX was then coupled to carboxylated MPEG-PCL through esterification (MPEG-PCL-PTX). MPEG-PCL-PTX micelles were prepared by a solvent evaporation method. Conjugation of PTX to MPEG-PCL-PTX was confirmed by 1H NMR. MPEG-PCL-PTX micelles self-assembled into micellar nanoparticles at concentrations above 2.5×10−2mg/mL, as evaluated by fluorescence spectrometry. DLS and TEM analyses revealed that the micelles were globular in shape with an average size of 111nm. The drug release studies under three pH conditions demonstrated that PTX release from MPEG-PCL-PTX micelles was entirely dependent upon the hydrolysis of ester bond between PTX and MPEG-PCL copolymer, therefore, no severe initial burst release but pH sensitive profile was observed. In vitro tests with the 4T1 cell line showed that conjugation of PTX to MPEG-PCL led to improved cellular uptake and apoptosis compared to free PTX, supporting the feasibility of using the micelles as drug carriers for cancer therapy.

Synthesis and biological evaluation of paclitaxel conjugates with prostate-specific membrane antigen inhibitor for the treatment of prostate cancer . .

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On-Demand Versatile Prodrug Nanomicelle for Tumor-Specific Bioimaging and Photothermal-Chemo Synergistic Cancer Therapy.

Photothermal therapy is a promising approach for antitumor application although regrettably restricted by available photothermal agents. Physical entrapment of organic near-infrared dyes into nanosystems was extensively studied to reverse the dilemma. However, problems still remained, such as drug bursting and leakage. We developed here an amphiphilic prodrug conjugate by chemically modifying indocyanine green derivative (ICG-COOH) and paclitaxel (PTX) to hyaluronic acid (HA) backbone for integration of photothermal-chemotherapy and specific tumor imaging. The prepared ICG-HA-PTX conjugates could self-assemble into nanomicelles to improve the stability and reduce systemic toxicity of the therapeutic agents. The high local concentration of ICG-COOH in nanomicelles resulted in fluorescence self-quenching, leading to no fluorescence signal being detected in circulation. When the nanomicelles reached the tumor site via electron paramagnetic resonance effect and HA-mediated active targeting, the overexpressed esterase in tumor cells ruptured the ester linkage between drugs and HA, achieving tumor-targeted therapy and specific imaging. A series of in vitro and in vivo experiments demonstrated that the easily prepared ICG- HA-PTX nanomicelles with high stability, smart release behavio r, and excellent tumor targeting ability showed formidable synergy in tumor inhibition, which provided new thoughts in developing an organic near-infrared-dye-based multifunctional delivery system for tumor theranostics.

CD44-Targeted Polymer-Paclitaxel Conjugates to Control the Spread and Growth of Metastatic Tumors.

One of the greatest challenges in cancer therapy is to control metastatic spread, seeding, and growth of tumors in distant organs. Recently, we reported on the design of a novel "drug-free" therapeutic copolymer bearing the antimigratory A5G27 peptide, designated P-(A5G27)-FITC, that shows excellent specificity to cancer cells overexpressing CD44v3 and CD44v6 and inhibits cancer cell migration and invasion. We demonstrated that P-(A5G27)-FITC accumulated preferentially in subcutaneous (sc) implanted 4T1 tumors following parenteral administration. Moreover, we showed that pretreatment of mice with P-(A5G27)-FITC prior to 4T1 cell inoculation inhibited colonization of circulating 4T1 cells in the lungs. In this study, we designed a new polymer-peptide-drug conjugate to inhibit vigorously growing primary tumors and control invasive behavior of cancer cells. To this end, the antimitotic drug (paclitaxel, PTX) was conjugated to P-(A5G27)-FITC. The targeted polymer-drug conjugate (P-(A5G27)-PTX) was significantly more toxic toward CD44-overexpressing cancer cells than the nontargeted copolymer. In vivo, a single iv injection of P-(A5G27)-PTX prolonged the survival of C57BL/6 mice with established B16-F10 lung metastases. When injected intraperitoneally into BALB/c mice implanted sc with 4T1 tumors, P-(A5G27)-PTX significantly decreased the rate of primary tumor growth, increased the median survival of mice, and reduced the number of 4T1 metastases in the lungs when compared to nontargeted copolymer. Most interestingly, the CD44-targeted "drug-free" copolymer P-(A5G27) (without PTX) significantly inhibited the rate of tumor growth and further prolonged the median survival time of mice to the same extent as the PTX-containing formulations (P-(A5G27)-PTX or free PTX). Overall, this study highlights the therapeutic potential of the HPMA copolymer-A5G27 conjugates ("drug-free" and PTX-bearing copolymers) to control the metastatic spread of cancer.

Delaying Anticancer Drug Delivery by Self-Assembly and Branching Effects of Minimalist Dendron-Drug Conjugates.

Self-assembly of a covalently-bound lipophilic drug to a dendronic scaffold for making organic nanoparticles is reported as a proof of concept in nanovectorization. A minimalist structural approach with a small PEG-dendron conjugated to paclitaxel (PTX), incorporating safe succinic and gallic acids, is efficient to provide the expected anticancer bioactivity, but also significantly retards and targets intracellular delivery of PTX in 2D and 3D lung cancer cell cultures. A branching effect of dendrons is crucial, when compared to linear PTX conjugates. Transmission electron microscopy (TEM) and dynamic light-scattering (DLS) studies indicate the formation of stable, low-disperse nanoparticles at 10-5 m in H2 0, which could also be responsible for the biological effects. An ultrasensitive LC-MS/MS method was used for the determination of intracellular PTX concentration over time, along with the survival rates of cancer cells. Similarly, cell survival assays were successfully correlated to a 3D cell culture with spheroids for mimicking tumors, when treated with PTX conjugates. Our work opens the way to a full evaluation program required for new chemical entities.

Synthesis and Biological Evaluation of Paclitaxel Conjugates Involving Linkers Cleavable by Lysosomal Enzymes and αVβ3‐Integrin Ligands for Tumor Targeting

Two cyclo[DKP‐RGD]‐PTX (PTX = paclitaxel) and two cyclo[RGDfK]‐PTX conjugates containing the Gly‐Phe‐Leu‐Gly (GFLG) linker, which is cleavable by lysosomal enzymes, were synthesized and compared to two cyclo[DKP‐RGD]‐Val‐Ala‐PTX conjugates. The conjugates were evaluated for their ability to inhibit biotinylated vitronectin binding to the isolated αvβ3 receptor, retaining good binding affinity, in the same nanomolar range of the free ligands. Cell viability assays were performed for the six conjugates in the αvβ3+ U87 and in the αvβ3– HT29 cell lines. Loss of potency was observed for all the conjugates, attenuated by the presence of a tetraethylene glycol (PEG‐4) spacer. A good Targeting Index (TI = Relative Potency in the αvβ3+ U87/Relative Potency in the αvβ3– HT29) was displayed by the conjugates, in particular by cyclo[DKP‐RGD]‐PEG‐4‐Val‐Ala‐PTX 9 (TI = 533). This conjugate was tested in the αvβ3+ U87 cell line in the presence of 50‐fold excess free cyclo[DKP‐RGD] ligand 2. In this competition experiment, a fivefold decrease of the conjugate cytotoxicity was calculated, suggesting that the conjugate is possibly internalized by an αvβ3 integrin‐mediated process.

Prostate-Specific Membrane Antigen Targeted Therapy of Prostate Cancer Using a DUPA–Paclitaxel Conjugate

Prostate cancer (PCa) is the most prevalent cancer among men in the United States and remains the second-leading cause of cancer mortality in men. Paclitaxel (PTX) is the first line chemotherapy for PCa treatment, but its therapeutic efficacy is greatly restricted by the nonspecific distribution in vivo. Prostate-specific membrane antigen (PSMA) is overexpressed on the surface of most PCa cells, and its expression level increases with cancer aggressiveness, while being present at low levels in normal cells. The high expression level of PSMA in PCa cells offers an opportunity for target delivery of nonspecific cytotoxic drugs to PCa cells, thus improving therapeutic efficacy and reducing toxicity. PSMA has high affinity for DUPA, a glutamate urea ligand. Herein, a novel DUPA-PTX conjugate is developed using DUPA as the targeting ligand to deliver PTX specifically for treatment of PSMA expressing PCa. The targeting ligand DUPA enhances the transport capability and selectivity of PTX to tumor cells via PSMA mediated endocytosis. Besides, DUPA is conjugated with PTX via a disulfide bond, which facilitates the rapid and differential drug release in tumor cells. The DUPA-PTX conjugate exhibits potent cytotoxicity in PSMA expressing cell lines and induces a complete cessation of tumor growth with no obvious toxicity. Our findings give new insight into the PSMA-targeted delivery of chemotherapeutics and provide an opportunity for the development of novel active targeting drug delivery systems for PCa therapy.

Treatment of oral cancer using magnetized paclitaxel

N,N’-Bis(salicylidene)ethylenediamine iron (Fe(Salen)) is an anti-cancer agent with intrinsic magnetic property. Here, we covalently linked Fe(Salen) to paclitaxel (PTX), a widely used anti-cancer drug, to obtain a magnetized paclitaxel conjugate (M-PTX), which exhibited magnetic characteristics for magnet-guided drug delivery and MRI visualization. M-PTX increased apoptosis and G2/M arrest of cultured human oral cancer cell lines in the same manner as PTX. Furthermore, marked contrast intensity was obtained in magnetic resonance imaging (MRI) of M-PTX. In a mouse oral cancer model, a permanent magnet placed on the body surface adjacent to the tumor resulted in distinct accumulation of M-PTX, and the anti-cancer effect was greater than that of M-PTX without the magnet. We believe that this strategy may improve future cancer chemotherapy by providing conventional anti-cancer drugs with novel functionalities such as magnet-guided drug delivery or MRI-based visualization/quantitation of drug distribution.

A robust control system for targeting melanoma by a supermolecular DDMC/paclitaxel complex.

A DEAE-dextran-MMA copolymer (DDMC)-paclitaxel (PTX) conjugate was prepared using PTX as the guest and DDMC as the host. The resistance of B16F10 melanoma cells to PTX was confirmed, while the DDMC-PTX conjugate showed excellent anticancer activity that followed the Hill equation. The robustness in the tumor microenvironment of the allosteric system was confirmed via BIBO stability. This feedback control system, explained via a transfer function, was very stable and showed the sustainability of the system via a loop, and it showed superior anti-cancer activity without drug resistance from cancer cells. The block diagram of this signal system in the tumor microenvironment used its loop transfer function G(s) and the dN(s) of the external force. This indicial response is an ideal one without a time lag for the outlet response. The cell death rate of DDMC-PTX is more dependent on the Hill coefficient n than on the Michaelis constant Km. This means that this supermolecular reaction with tubulin follows an "induced fit model".

Nitrogen-doped Carbon Nanodots for bioimaging and delivery of paclitaxel

Carbon nanodots (CNDs) hold great potential in imaging and drug delivery applications. In this study, nitrogen-doped CNDs (NCNDs) were coupled to the anticancer agent paclitaxel (PTX) through a labile ester bond. NCNDs showed excellent cell viability and endowed the NCND–PTX conjugate with good water solubility. The hybrid integrates the optical properties of the nanodots with the anticancer function of the drug into a single unit. Cytotoxicity was evaluated in breast, cervix, lung, and prostate cancer cell lines by the MTT assay while the cellular uptake was monitored using confocal microscopy. NCND–PTX induced apoptosis in cancer cells exhibiting slightly better anticancer activity compared to the drug alone. Moreover, the course of the NCND–PTX interaction with cancer cells was monitored using an xCELLigence system. The NCND-based conjugate represents a promising platform for bioimaging and drug delivery.

Near-infrared BODIPY-paclitaxel conjugates assembling organic nanoparticles for chemotherapy and bioimaging

Self-assembly of organic molecules has attracted more and more attention because of precise molecular structure and multifarious synthesis chemistry. Herein, near-infrared brominated boron-dipyrromethenes (BODIPY) paclitaxel conjugate (BrBDP-2PTX) was synthesized. BrBDP-2PTX could self-assemble into uniform spherical nanoparticles (BrBDP-2PTX NPs) via nanoprecipition method. The obtained nanoparticles showed satisfying stability in aqueous solution and 10% fetal bovine serum (FBS) containing phosphoric acid buffer solution (PBS). Moreover, BrBDP-2PTX NPs could make rapid enzyme response to Proteinase K as evidenced by the obvious changes in size and size distribution. BrBDP-2PTX NPs could be internalized by the HeLa cells and exhibited potent cytotoxicity toward tumor cells (human cervical carcinoma cells and liver hepatocellular carcinoma cells) as revealed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays and live/dead staining. Furthermore, in vivo experiments indicated BrBDP-2PTX NPs could be used as efficient bioimaging agents without causing any systemic toxicity. This work highlights the potential of using self-assembly of small organic molecules to develop functional nanomaterials.

Wilms Tumor NCAM-Expressing Cancer Stem Cells as Potential Therapeutic Target for Polymeric Nanomedicine.

Cancer stem cells (CSC) form a specific population within the tumor that has been shown to have self-renewal and differentiation properties, increased ability to migrate and form metastases, and increased resistance to chemotherapy. Consequently, even a small number of cells remaining after therapy can repopulate the tumor and cause recurrence of the disease. CSCs in Wilms tumor, a pediatric renal cancer, were previously shown to be characterized by neural cell adhesion molecule (NCAM) expression. Therefore, NCAM provides a specific biomarker through which the CSC population in this tumor can be targeted. We have recently developed an NCAM-targeted nanosized conjugate of paclitaxel bound to a biodegradable polyglutamic acid polymer. In this work, we examined the ability of the conjugate to inhibit Wilms tumor by targeting the NCAM-expressing CSCs. Results show that the conjugate selectively depleted the CSC population of the tumors and effectively inhibited tumor growth without causing toxicity. We propose that the NCAM-targeted conjugate could be an effective therapeutic for Wilms tumor. Mol Cancer Ther; 16(11); 2462-72. ©2017 AACR.

Caveolae-Mediated Endocytosis Is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy.

Nab-paclitaxel, a nanoparticle conjugate of paclitaxel to human albumin, exhibits efficacy in pancreatic cancer, non-small cell lung cancer and breast cancer. However, there is a lack of predictive biomarkers to identify patients who might benefit most from its administration. This study addresses this gap in knowledge by identifying that caveolin-1 (Cav-1) is a candidate mechanism-based biomarker. Caveolae are small membrane invaginations important for transendothelial albumin uptake. Cav-1, the principal structural component of caveolae, is overexpressed in the cancers noted above that respond to nab-paclitaxel. Thus, we hypothesized that Cav-1 may be critical for albumin uptake in tumors and perhaps determine their response to this drug. Cav-1 protein levels correlated positively with nab-paclitaxel sensitivity. RNAi-mediated attenuation of Cav-1 expression reduced uptake of albumin and nab-paclitaxel in cancer cells and rendered them resistant to nab-paclitaxel-induced apoptosis. Conversely, Cav-1 overexpression enhanced sensitivity to nab-paclitaxel. Selection for cellular resistance to nab-paclitaxel in cell culture correlated with a loss of Cav-1 expression. In mouse xenograft models, cancer cells, where Cav-1 was attenuated, exhibited resistance to the antitumor effects of nab-paclitaxel therapy. Overall, our findings suggest Cav-1 as a predictive biomarker for the response to nab-paclitaxel and other albumin-based cancer therapeutic drugs. Cancer Res; 77(21); 5925-37. ©2017 AACR.