Polymeric Paclitaxel Research Articles

Physicochemical properties and biocompatibility of a polymer-paclitaxel conjugate for cancer treatment

BackgroundPoly(L-γ-glutamylglutamine) paclitaxel (PGG-PTX) conjugate is a non-diblock polymeric drug nanoparticle intended to improve the therapeutic index of paclitaxel. The purpose of the present study was to elucidate further the physicochemical properties of PGG-PTX in order to proceed with its clinical development.Methods and resultsPGG-PTX was designed by integration of a hydrophobic paclitaxel conjugate through an added hydrophilic glutamic acid onto poly(L-glutamic acid). The addition of a flexible glutamic linker between PGA and paclitaxel resulted in spontaneous self-assembly of a PGG-PTX conjugate into nanoparticles. The PGG-PTX conjugate was stable as a lyophilized solid form. An in vitro viability experiment showed that PGG-PTX was effective after a longer incubation period, the same trend as Taxol. In vitro studies using NCI-H460 and B16F0 cancer cells demonstrated significantly high cellular uptake after 30 minutes of incubation. The in vivo biocompatibility of PGG-PTX conjugate was evaluated in the NCI-H460 tumor model, the assessment of tissue seemed to be normal after 21 days of treatment.ConclusionThese results are encouraging for further development of non-block polymeric paclitaxel nanoparticles for treatment of cancer.

Clinically relevant anticancer polymer Paclitaxel therapeutics.

The concept of utilizing polymers in drug delivery has been extensively explored for improving the therapeutic index of small molecule drugs. In general, polymers can be used as polymer-drug conjugates or polymeric micelles. Each unique application mandates its own chemistry and controlled release of active drugs. Each polymer exhibits its own intrinsic issues providing the advantage of flexibility. However, none have as yet been approved by the U.S. Food and Drug Administration. General aspects of polymer and nano-particle therapeutics have been reviewed. Here we focus this review on specific clinically relevant anticancer polymer paclitaxel therapeutics. We emphasize their chemistry and formulation, in vitro activity on some human cancer cell lines, plasma pharmacokinetics and tumor accumulation, in vivo efficacy, and clinical outcomes. Furthermore, we include a short review of our recent developments of a novel poly(l-γ-glutamylglutamine)-paclitaxel nano-conjugate (PGG-PTX). PGG-PTX has its own unique property of forming nano-particles. It has also been shown to possess a favorable profile of pharmacokinetics and to exhibit efficacious potency. This review might shed light on designing new and better polymer paclitaxel therapeutics for potential anticancer applications in the clinic.

A Case of Ischemic Colitis Associated with Paclitaxel Loaded Polymeric Micelle (Genexol-PM®) Chemotherapy

Paclitaxel has been widely used for treating many solid tumors. Although colonic toxicity is an unusual complication of paclitaxel-based chemotherapy, the reported toxicities include pseudomembranous colitis, neutropenic enterocolitis and on rare occasions ischemic colitis. , which is a recently developed cremophor-free, polymeric micelle-formulated paclitaxel, has shown a more potent antitumor effect because it can increase the usual dose of paclitaxel due to that does not include the toxic cremophor compound. We report here on a case of a 57-year-old man with advanced non-small cell lung cancer and who developed ischemic colitis after chemotherapy with and cisplatin. He complained of hematochezia with abdominal pain on the left lower quadrant. Colonoscopy revealed diffuse mucosal hemorrhage and edema from the sigmoid colon to the splenic flexure. After bowel rest, he recovered from his symptoms and the follow-up colonoscopic findings showed that the mucosa was healing. Since then, he was treated with pemetrexed monotherapy instead of a paclitaxel compound and platinum.

Thermosensitive poly(organophosphazene)–paclitaxel conjugate gels for antitumor applications

A poly(organophosphazene)–PTX conjugate was synthesized by a covalent ester linkage between PTX and carboxylic acid-terminated poly(organophosphazene), which can be readily modified by various hydrophobic, hydrophilic, and other functional substitutes. The physicochemical properties, hydrolytic degradation and PTX release behaviors of the polymer–PTX conjugate were characterized, in addition to the in vitro and in vivo antitumor activities. The aqueous solutions of these conjugates showed a sol–gel transition behavior that depended on temperature changes. The in vitro antitumor activity of the polymer–PTX conjugate was investigated by an MTT assay against human tumor cell lines. From the in vivo antitumor activity studies with tumor-induced (xenografted) nude mice, the polymer–paclitaxel conjugate hydrogels after local injection at the tumor site were shown to inhibit tumor growth more effectively and longer than paclitaxel and saline alone, indicating that the tumor-active paclitaxel from the polymer–PTX conjugate hydrogel is released slowly over a longer period of time and effectively accumulated locally in the tumor sites. These combined observations suggest that this poly(organophosphazene)–PTX conjugate holds promise for use in clinical studies as single and/or combination therapies.

Paclitaxel tumor biodistribution and efficacy after intratumoral injection of a biodegradable extended release implant

Purpose The aim of this study was to investigate the effectiveness of paclitaxel controlled release from intratumorally injected polymer. Methods The effectiveness of paclitaxel–polymer formulation injected intratumorally was tested in mouse bladder tumor model. To determine paclitaxel biodistribution in tumor at predetermined time periods the tumor was excised, frozen and sectioned, and the paclitaxel concentrations were determined in the tumor tissue and in plasma by HPLC. Histopathological evaluation of the necrosis and inflammation was performed on tumor sections. Results In the paclitaxel/polymer group mice were injected intratumorally with 0.2 ml of the 10% (w/w) paclitaxel formulation, the tumor disappeared completely 5 days after injection, and mice survived till the end of the study (50 days post-tumor cells inoculation). In biodistribution studies, the highest paclitaxel concentration in the tumor tissue was 40 μg/mg 1 day after the intratumoral injection and decreased gradually during 10 days to 5 μg/mg that is still high enough to induce cytotoxic effect, and the necrotic effect of paclitaxel on the tumors was confirmed by histopathology. Conclusions Treatment with local injection of polymer–paclitaxel formulation inhibited the growth of solid tumors. Distribution studies of paclitaxel after intratumoral injection showed high and effective drug concentrations in tumor.

Intratumoral delivery of paclitaxel-loaded poly(lactic-co-glycolic acid) microspheres for Hep-2 laryngeal squamous cell carcinoma xenografts

The introduction of induction chemotherapy provides an expectation of laryngeal function preservation without reduction in survival for patients with advanced laryngeal squamous cell carcinoma. The antitumor activity of conventional intravenous chemotherapy, however, is limited by systemic toxicity. The polymeric drug system delivered locally provides a novel modality of increasing therapeutic concentrations of drug for a prolonged period while decreasing systemic levels. In the current study, paclitaxel-loaded sustained-release microspheres were developed using poly(lactic-co-glycolic acid) as a drug carrier. Intratumoral administration of paclitaxel in the formulation of polymer showed enhanced efficacy against laryngeal squamous cell carcinoma in nude mice compared with conventional paclitaxel injection via the intratumoral or intraperitoneal route. No significant toxic reactions were observed in the experiment. Immunohistochemical findings indicated that paclitaxel exhibited antiangiogenic activity by inhibiting the expression of basic fibroblast growth factor and vascular endothelial growth factor within the tumor. Moreover, this effect could be better exploited via localized delivery of polymeric paclitaxel. In conclusion, direct administration of polymeric drug system at the tumor sites proved to be promising for the treatment of laryngeal carcinoma.

Incidence, Timing, and Correlates of Stent Thrombosis With the Polymeric Paclitaxel Drug-Eluting Stent: A TAXUS II, IV, V, and VI Meta-Analysis of 3,445 Patients Followed for Up to 3 Years

This study sought to study stent thrombosis with the paclitaxel-eluting Taxus stent. The incidence and timing of stent thrombosis after drug-eluting stent placement compared with bare-metal stent implantation remain unsettled, with consequent uncertainty about risk stratification and long-term recommendations for antiplatelet medications. This study used a patient-based meta-analysis using the 4 principal TAXUS randomized trials (3,445 patients) with a follow-up duration of ≥1 year. Cumulative stent thrombosis occurred in 1.28% ± 0.31% in the Taxus group and 0.76% ± 0.23% in the bare-metal stent group at 3 years (hazard ratio 1.51 [95% confidence interval 0.73 to 3.14], p = 0.26). Hazard ratios (per 100 patients per 6 months) were similar between the Taxus stent group (0.59 [95% confidence interval 0.22 to 0.95]) and the bare-metal stent group (0.64 [95% confidence interval 0.26 to 1.02]) through 6 months during the prescribed clopidogrel period. However, from 6 months to 3 years there were more stent thromboses in the Taxus group (hazard ratio 0.19 [95% confidence interval 0.06 to 0.32] vs. 0.02 [95% confidence interval 0.00 to 0.07], p = 0.049). Of 8 patients with Taxus-related thrombosis after 6 months, 0 were taking clopidogrel and 2 were not taking aspirin consistently. No Taxus-related stent thrombosis occurred after 2 years (922 patients thus far followed up for 3 years). Independent correlates of stent thrombosis were nonuse of clopidogrel, male gender, smoking, and possibly use of multiple nonoverlapping stents. Approximately 0.8% of Taxus patients have stent thrombosis in the first 6 months after stent implantation, similar to bare-metal stents. However, a modest increase in risk is present with Taxus stents beyond 6 months, possibly because of inadequate antiplatelet drug therapy.

A novel polymer–paclitaxel conjugate based on amphiphilic triblock copolymer

A novel amphiphilic polymer–paclitaxel conjugate P(LGG-paclitaxel)-PEG-P(LGG-paclitaxel) has been prepared. It was derived from its parent polymer P(LGG)-PEG-P(LGG), poly{(lactic acid)- co-[(glycolic acid)- alt-( l-glutamic acid)]}- block-poly(ethylene glycol)- block-poly{(lactic acid)- co-[(glycolic acid)- alt-( l-glutamic acid)]}, which was prepared by ring-opening copolymerization of l-lactide (LLA) with (3s)-benzoxylcarbonylethyl-morpholine-2,5-dione (BEMD) in the presence of dihydroxyl PEG with molecular weight of 4600 as a macroinitiator using stannous octoate (Sn(Oct) 2) as catalyst, and by subsequent catalytic hydrogenation. It could self-assemble into micelles in an aqueous system with P(LGG-paclitaxel) block in the core and PEG in the shell. ESEM and DLS analysis of the micelles revealed a homogeneous spherical morphology and a unimodal size distribution. In vitro release of paclitaxel from the conjugate micelles showed that its release rate depended on pH value and was higher at lower pH than in neutral condition. In vitro antitumor activity of the paclitaxel conjugate against rat brain glioma C6 cells was evaluated by MTT method. The results showed that the paclitaxel can be released from the conjugate without losing cytotoxicity.

Multicenter phase II study of a cremophor-free polymeric micelle-formulated paclitaxel in patients (pts) with metastatic breast cancer (MBC)

10520 Background: The results of a phase I trial of a novel taxane, a cremophor-free polymeric micelle-formulated paclitaxel (Genexol-PM), were previously reported (Clin Cancer Res 10:3708, 2004). The dose limiting toxicities were neuropathy, myalgia, and neutropenia. Notably, acute hypersensitivity reaction was not observed. Methods: This was a single arm phase II study performed at 6 major hospitals in Korea to evaluate the efficacy and safety of Genexol-PM as a 1st- or 2nd-line therapy for MBC. Genexol-PM with no premedication was given at 300 mg/m2 i.v. over 3 hr on day 1 every 3 weeks until disease progression or intolerability. Two-stage group sequential design was used. If more than 14 responses were attained in the first 30 pts, early termination was possible. Results: Forty-three pts with MBC were enrolled from 7/2004 to 12/2004. Median follow-up duration was 7.0 mo. Thirty-seven of 41 pts excluding 2 pts who did not receive Genexol-PM received Genexol-PM as a first-line therapy. Nineteen pts received prior anthracycline containing regimen in adjuvant (15) and in metastatic (4) settings. No pts were anthracycline-resistant. Median age was 48 years (range; 30 to 69 years) with ECOG PS 0 or 1. A total of 331 cycles were administered, with median of 8 per patient (range; 1 to 16). Of 39 pts evaluable for efficacy, there were 5 CRs /19 PRs with response rate of 61.5%, 13 SDs and 2 PDs. Median response duration was not reached (range; 1.9+ to 10.0+ mo). Median TTP and OS were 9.8 and 11.2 mo, respectively. G3 non-hematologic toxicities included peripheral sensory neuropathy (51.2%) and myalgia (2.4%). Hematologic toxicities were G3/G4 neutropenia (51.2%, 17.1%, respectively) and G1/2 thrombocytopenia (22.0%). Seventeen pts (41.5%) required dose reductions due to G3 neuropathy. No febrile neutropenia was observed. Eight pts developed hypersensitivity reactions with G3 in 2 pts. Mean dose intensity (DI) was 87.4 mg/m2/wk (range; 27.7 to 116.7) at 87.4% of planned DI. Conclusions: Genexol-PM at 300 mg/m2 appears a promising agent with high response rate for anthracycline sensitive MBC. Further trials at a different dose schedule or duration of delivery, or in combination with other drugs are warranted. Supported by Samyang Co, Korea. No significant financial relationships to disclose.

A pharmacokinetic and safety study of a novel polymeric paclitaxel formulation for oral application

To investigate the pharmacokinetics, safety, and tolerability of a new oral formulation of paclitaxel containing the polymer polyvinyl acetate phthalate in patients with advanced solid tumors. A total of six patients received oral paclitaxel as single agent given as a single dose of 100 mg on day 1, oral paclitaxel 100 mg in combination with cyclosporin A (CsA) 10 mg/kg both given as a single dose on day 8, and i.v. paclitaxel (Taxol) 100 mg as a 3-h infusion on day 15. The AUC (mean +/- standard deviation) values of paclitaxel after oral administration without CsA and with CsA were 476 +/- 254 and 967 +/- 779 ng/ml h, respectively. T (max) was 4.0 +/- 0.9 h after oral paclitaxel without CsA, and 6.0 +/- 3.1 h after oral paclitaxel with CsA. The mean AUC after oral administration as single agent was 13% of the AUC after i.v. administration of paclitaxel, and increased to 26% after co-administration with CsA. No haematological toxicities were observed, and only mild (CTC-grade 1 and 2) non-hematological toxicities occurred after oral intake of paclitaxel with or without CsA. The AUC of the new polymeric paclitaxel formulation increased a factor 2 in combination with CsA, which confirms that CsA co-administration can also improve exposure to paclitaxel after oral administration of a polymeric formulation. Because of the delayed release of paclitaxel from this formulation, we hypothesize that a split-dose regimen of CsA where it is administered before and after paclitaxel administration will further increase the systemic exposure to paclitaxel up to therapeutic levels. The formulation was well tolerated at the dose of 100 mg without induction of severe toxicities.

An investigation of the antitumour activity and biodistribution of polymeric micellar paclitaxel.

To evaluate in vitro cytotoxicity, in vivo antitumour activity and biodistribution of a novel polymeric (poly(DL-lactide)-block-methoxy polyethylene glycol) micellar paclitaxel. Hs578T breast, SKMES non-small-cell lung, and HT-29 colon human tumour cells were exposed, either for 1 h or continuously, to conventionally formulated paclitaxel (Cremophor paclitaxel) or polymeric micellar paclitaxel. After a period of incubation, cytotoxicity was measured using a radiometric system. In the in vivo antitumour study, B6D2F1 mice, bearing P388 leukaemia tumour intraperitoneally (i.p.), were treated with polymeric micellar paclitaxel or Cremophor paclitaxel by i.p. injection. The number of deaths and body weights were recorded. In the biodistribution study, CD-1 mice were given micellar paclitaxel i.p. at a dose of 100 mg/kg. The mice were sacrificed after a given time and the organs were harvested. Paclitaxel in the organs was extracted by acetonitrile and analysed using HPLC. The polymeric micellar paclitaxel showed similar in vitro cytotoxicity to Cremophor paclitaxel against the tumour cell lines. The polymeric micellar formulation of paclitaxel produced a fivefold increase in the maximum tolerated dose (MTD) as compared with Cremophor paclitaxel when administered i.p. In addition, micellar paclitaxel was more efficacious in vivo when tested in the murine P388 leukaemia model of malignancy than Cremophor paclitaxel when both were administered i.p. at their MTDs. Micellar paclitaxel-treated animals had an increased survival time and, importantly, long-term survivors (20% of those tested) were obtained only in the polymeric paclitaxel formulation group. Biodistribution studies indicated that a significant amount of paclitaxel could be detected in blood, liver, kidney, spleen, lung and heart of mice after i.p. dosing of the polymeric micellar paclitaxel formulation. These preliminary results indicate that polymeric micellar paclitaxel could be a clinically useful chemotherapeutic formulation.