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Designing Paclitaxel drug delivery systems aimed at improved patient outcomes: current status and challenges.

ISRN Pharmacol. 2012;2012:623139

Authors: Surapaneni MS, Das SK, Das NG

Abstract
Paclitaxel is one of the most widely used and effective antineoplastic agents derived from natural sources. It has a wide spectrum of antitumor activity, particularly against ovarian cancer, breast cancer, nonsmall cell lung cancer, head and neck tumors, Kaposi's sarcoma, and urologic malignancies. It is a highly lipophilic compound with a log P value of 3.96 and very poor aqueous solubility of less than 0.01 mg/mL. In addition, the compound lacks functional groups that are ionizable which could potentially lead to an increase in its solubility with the alteration in pH. Therefore, the delivery of paclitaxel is associated with substantial challenges. Until the introduction of Abraxane, only commercial formulation was solution of paclitaxel in cremophor, which caused severe side effects. However, in recent years, a number of approaches have been reported to solubilize paclitaxel using cosolvents and inclusion complexes. In addition, innovative approaches have been reported for passive targeting of tumors using nanoparticles, nanosuspensions, liposomes, emulsions, micelles, implants, pastes and gels. All approaches for delivery of improved therapeutic outcome have been discussed in this paper.

PMID: 22934190 [PubMed]

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Cancer Lett. 2012 Aug 27;
Authors: Maksimenko A, Mougin J, Mura S, Sliwinski E, Lepeltier E, Bourgaux C, Lepêtre S, Zouhiri F, Desmaële D, Couvreur P

A series of new polyisoprenoyl prodrugs of gemcitabine, which can be formulated as nanoassemblies are described. These prodrugs were designed to improve gemcitabine efficacy and to overcome the limitations due to the systemic toxicity of this anticancer compound. In vitro biological assessment showed that these polyisoprenoyl gemcitabine nanoassemblies displayed notable cytotoxicity on several cancer cell lines, including murine melanoma cell line B16F10, human pancreatic carcinoma cell line MiaPaCa-2, human lung carcinoma cell line A549 and human breast adenocarcinoma cell line MCF7. Interestingly, it was observed that the anticancer efficacy of these nanoassemblies was dependant on the size of polyisoprenoyl moiety. The polyisoprenoyl prodrug of gemcitabine containing three isoprene units (2d) was the more active on all the cancer cell lines tested. The antitumor efficacy of the nanoassemblies (NAs) constructed with the most active prodrug 2d was further evaluated on a human pancreatic (MiaPaCa-2) carcinoma xenograft model in mice. The prodrug 2d NAs showed an increased antitumor efficacy as compared to free gemcitabine or to squalene-gemcitabine (SQ-gem, 2a) nanoassemblies. Interestingly, MiaPaCa-2 tumors that did not respond to gemcitabine were inhibited by 76% after treatment with prodrug 2d NAs, whereas SQ-gem-treated MiaPaCa-2 tumor xenografts decreased only by 41% compared to saline or to gemcitabine-treated mice. Together, these findings demonstrated that the modulation of the length of nanoassemblies polyisoprenoyl moiety made tumor cells more sensitive to gemcitabine treatment without flagrant toxicity, thus providing a significant improvement in the drug therapeutic index.

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Chin J Integr Med. 2012 Sep;18(9):663-9
Authors: Feng Y, Xiao YY, Li SD, Lin MX, Zhang Y, Wang HM, Li M, Zhang X, Cao K, Ye YF, Zhao L

OBJECTIVE: To investigate the effects of brachytherapy with computed tomography-guided percutaneous radioactive I-125 seeds interstitial implantation (ISI) synchronized chemotherapy and Chinese medicine (CM) for the treatment of advanced stage of non-small cell lung cancer (NSCLC).
METHODS: Ninety patients diagnosed with NSCLC by biopsy were randomly assigned to three groups: the synchronized therapy group (A), the chemotherapy plus CM-treated group (B), and the chemotherapy-treated group (C); a 2-month course of treatment was administered to them all. The effectiveness of treatment was evaluated based on tumor size, tumor markers (carcinoembryonic, squamous cell carcinoma-associated antigen, and cytokeratin 19 fragment), clinical symptoms, and quality of life (QOL) in patients.
RESULTS: The total effective rates of Groups A to C were 83.33%, 46.67%, and 43.33%, respectively. The tumor markers were reduced obviously in Group A, showing signifificant difference compared with those in the other two groups. Additionally, QOL was elevated and cancer-related symptoms were alleviated more signifificant in Group A than those in Group C (all P<0.05).
CONCLUSION: The synchronized therapy of I-125 implantation with chemotherapy and CM was a safe therapeutic method and can be regarded as a new mode for treatment of advanced-stage NSCLC.

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Support Care Cancer. 2012 Aug 31;
Authors: Jiang N, Chen XC, Zhao Y

Myelosuppression induced by concurrent chemotherapy and radiotherapy can be a significant problem in patients with non-small cell lung cancer (NSCLC), but its risk factors remain largely unknown. The objective of this study was to retrospectively evaluate clinical data obtained before chemoradiotherapy (CRT) to identify the risk factors for myelosuppression in patients with advanced NSCLC. METHODS: Between January 2007 and January 2012, 141 patients with advanced NSCLC were treated with curative intent according to the CRT protocol (50-70 Gy at 2 Gy/day with paclitaxel 135-175 mg/m(2) and carboplatin 100 mg/m(2) on days 1, 22, and 43). The endpoint of this survey was the occurrence of grade 3 or higher myelosuppression (neutropenia, leukopenia, thrombocytopenia, or anemia). Risk factors significantly related to myelosuppression were extracted using logistic regression analysis. RESULTS: Grade 3 or higher neutropenia, leukopenia, thrombocytopenia, or anemia occurred in 19.9, 16.3, 14.9, and 0 % of the patients, respectively. According to the multivariate analysis, the risk factors included age, albumin, and body surface area (BSA) for neutropenia; performance status and bone metastases for leukopenia; and age, gender, and serum creatinine concentration for thrombocytopenia (p < 0.05). CONCLUSIONS: It was found that age, BSA, creatinine level, and female gender were the most important factors for CRT-induced myelosuppression in advanced NSCLC. By identifying these risk factors, medical staff can improve application of appropriate medical care to reduce the myelosuppression in advanced NSCLC patients treated by CRT.