Co-Delivery of Gemcitabine and Paclitaxel in cRGD-Modified Long Circulating Nanoparticles with Asymmetric Lipid Layers for Breast Cancer Treatment

Abstract

Combination chemotherapy is a common clinical practice in cancer treatment. Here, cyclic RGD (arginylglycylaspartic acid) peptide was introduced to the surface of lipid/calcium/phosphate (LCP) asymmetric lipid layer nanoparticles for the co-delivery of paclitaxel (PTX) and gemcitabine monophosphate (GMP) (P/G-NPs). The sphere-like morphology of P/G-NPs displays a well-distributed particle size, and high entrapment efficiency and drug loading for both PTX and GMP, with a positive zeta potential. P/G-NPs were stable for up to 15 days. The cellular uptake of these cyclic RGD-modified nanoparticles was significantly higher than that of unmodified nanoparticles over 2 h incubation. Compared with the combination of free PTX and GMP (P/G-Free), P/G-NPs exhibited a longer circulation lifetime and improved absorption for PTX and GMP. Polyethylene glycol was responsible for a higher plasma concentration and a decreased apparent volume of distribution (Vz). Nanoparticles enhanced the drug accumulation in tumors compared with other major organs after 24 h. P/G-NPs nearly halted tumor growth, with little evidence of general toxicity, whereas P/G-Free had only a modest inhibitory effect at 16 mg/kg of GMP and 2.0 mg/kg of PTX. Increased levels of apoptosis within tumors were detected in P/G-NPs group by approximately 43.6% (TUNEL assay). When compared with GMP NPs, PTX NPs, and P/G-Free, P/G-NPs decreased expression of B-cell lymphoma-2 and B-cell lymphoma-extra large proteins, and increased expression of cleaved poly-ADP-ribose polymerase-1. Calreticulin expression in tumors also increased upon the co-delivery of PTX and GMP. The antitumor effect of P/G-NPs is more powerful than P/G-Free, GMP NP, or PTX NP alone, without obvious toxicity.

Novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis

“…While the exact mechanisms leading to this enhanced therapeutic index is not clear, it is likely through enhancement in differential drug distribution and pharmacokinetic profile. With two drugs in one intravenous injection, the DcNP formulation has prolonged the apparent elimination half-life of gemcitabine by more than 8× and enhanced its AUC by nearly 60×, higher than known previous achievements [17,18]. Such enhancement may owe to association to DcNP, together with reduced paclitaxel clearance; plus potentially prevent exposure of DcNP bound gemcitabine inactivation by cytidine deaminase (to 2',2'-difluorodeoxyuridine, or dFdU) in liver and cells [19].…”

<p>A Gastric Cancer Peptide GX1-Modified Nano-Lipid Carriers Encapsulating Paclitaxel: Design and Evaluation of Anti-Tumor Activity</p>

“…In order to further observe the cellular uptake of GX1modified nanoparticles on MKN45 and Co-HUVEC cells, NLCs containing 6C instead of PTX were prepared. 51 The results showed that the uptake rates of the PTX and the two NLCs by Co-HUVEC cells were in the order of GX1-6C-NLCs > 6C-NLCs > free 6C, while the GX1-6C-NLCs and 6C-NLCs had no significant difference uptake effect on MKN45. The results of the cellular uptake study were consistent with those from the CCK8 assay, indicating that GX1 can increase the selective adsorption ability of nanoparticles to Co-HUVEC cells.…”

Drug Resistance in Metastatic Breast Cancer: Tumor Targeted Nanomedicine to the Rescue

“…This resulted in reduction of lung and liver metastasis of breast cancer in vivo [ 134 ]. RGD peptide functionalized NPs can be a useful tool to delivery chemotherapy drugs, such as Doxorubicin (DOX) and Paclitaxel (PTX) [ 141 , 142 ]. Figure 4 B illustrates cancer cells targeting achieved by active drug delivery mechanisms [ 25 ].…”