Superior therapeutic efficacy of nab-paclitaxel over cremophor-based paclitaxel in locally advanced and metastatic models of human pancreatic cancer

Abstract

Background:Albumin-bound paclitaxel (nab-paclitaxel, nab-PTX) plus gemcitabine (GEM) combination has demonstrated efficient antitumour activity and statistically significant overall survival of patients with metastatic pancreatic ductal adenocarcinoma (PDAC) compared with GEM monotherapy. This regimen is currently approved as a standard of care treatment option for patients with metastatic PDAC. It is unclear whether cremophor-based PTX combined with GEM provide a similar level of therapeutic efficacy in PDAC.Methods:We comprehensively explored the antitumour efficacy, effect on metastatic dissemination, tumour stroma and survival advantage following GEM, PTX and nab-PTX as monotherapy or in combination with GEM in a locally advanced, and a highly metastatic orthotopic model of human PDAC.Results:Nab-PTX treatment resulted in significantly higher paclitaxel tumour plasma ratio (1.98-fold), robust stromal depletion, antitumour efficacy (3.79-fold) and survival benefit compared with PTX treatment. PTX plus GEM treatment showed no survival gain over GEM monotherapy. However, nab-PTX in combination with GEM decreased primary tumour burden, metastatic dissemination and significantly increased median survival of animals compared with either agents alone. These therapeutic effects were accompanied by depletion of dense fibrotic tumour stroma and decreased proliferation of carcinoma cells. Notably, nab-PTX monotherapy was equivalent to nab-PTX plus GEM in providing survival advantage to mice in a highly aggressive metastatic PDAC model, indicating that nab-PTX could potentially stop the progression of late-stage pancreatic cancer.Conclusions:Our data confirmed that therapeutic efficacy of PTX and nab-PTX vary widely, and the contention that these agents elicit similar antitumour response was not supported. The addition of PTX to GEM showed no survival advantage, concluding that a clinical combination of PTX and GEM may unlikely to provide significant survival advantage over GEM monotherapy and may not be a viable alternative to the current standard-of-care nab-PTX plus GEM regimen for the treatment of PDAC patients.

In vivo metabolic and SHG imaging for monitoring of tumor response to chemotherapy

“…For example, a reduction in stromal (Type I collagen) content was detected in nab-paclitaxel treated pancreatic cancer in mouse models (34). This effect, however, was not observed in paclitaxel-treated tumors (36). This effect, however, was not observed in paclitaxel-treated tumors (36).…”

“…Chen et al showed that conventional cremophor-based paclitaxel attenuates the generation of collagen, and of collagen lattice contraction in human fibroblasts in vitro (35). This effect, however, was not observed in paclitaxel-treated tumors (36).…”

Nanomedicines for renal disease: current status and future applications

“…Over a dozen NP platforms based on liposomes 29–45 , albumin 46–51 , polymeric micelles 52–58 , and nanosized polymer-drug conjugates 59–62 have been approved by the FDA (TABLE 1). A few targeted NPs including Her2 scFv-targeted liposomes (MM-302) 63 , the first targeted controlled-release polymeric NP BIND-014 (REF.…”

Combination Chemotherapy Regimens in Pancreatic Cancer

“…Кроме того, выявлен синер-гизм между nab-паклитакселом и гемцитабином. На орто-топических моделях местнораспространенного (Panc185) и метастатического (Panc265) РПЖ было показано, что частота полного ответа опухоли при лечении мышей ком-бинацией гемцитабина с nab-паклитакселом выше, чем при лечении комбинацией гемцитабина с паклитакселом (89 и 22% соответственно) [31]. Это отчасти связано с тем, что nab-паклитаксел в отличие от паклитаксела вызывает истощение обильной десмопластической стромы опухо-ли, характерной для РПЖ и участвующей в прогрессии опухоли и химиорезистентности.…”

“…Это отчасти связано с тем, что nab-паклитаксел в отличие от паклитаксела вызывает истощение обильной десмопластической стромы опухо-ли, характерной для РПЖ и участвующей в прогрессии опухоли и химиорезистентности. В итоге концентрация гемцитабина в опухолевой ткани увеличивалась почти в 3 раза [31][32][33].…”