Antibody Conjugated PLGA Nanoparticles for Targeted Delivery of Paclitaxel Palmitate: Efficacy and Biofate in a Lung Cancer Mouse Model

Abstract

Aberrant signaling of the epidermal growth factor receptor (EGFR) is common to a variety of human cancers and is also found to be over-expressed in most cases of non-small cell lung cancer. For the development of a molecularly targeted therapy, cetuximab-conjugated nanoparticles (immunonanoparticles, INPs) are designed and loaded with the lipophilic paclitaxel palmitate (pcpl) prodrug. Oleyl cysteineamide (OCA) is synthesized whereby its amphiphilic nature enables interfacial anchoring and thiol surface functionalization of PLGA NPs, facilitating bioconjugation to cetuximab by thioether bonds. It is demonstrated that the in vitro targeting efficiency and improved cellular internalization and cytotoxicity of this targeted delivery system in lung cancer cells over-expressing EGFR. A quantitative measure of the high binding affinity of INPs to EGFR is demonstrated using surface plasmon resonance. In vivo tolerability and enhanced efficacy of cetuximab pcpl INPs in a metastatic lung cancer model are reported. Its therapeutic efficacy in A549-luc-C8 lung tumors is shown using non-invasive bioluminescent imaging. Intravenous administration of cetuximab pcpl INPs to mice results in significantly higher inhibition of tumor growth and increased survival rates as compared to the non-targeted drug solution, drug-loaded nanoparticles or blank INPs. Pharmacokinetics and organ biodistribution of the prodrug and parent drug are evaluated by LC-MS/MS in lung tumor bearing mice. No enhanced total accumulation of nanoparticles or INPs is found at the tumor tissue. However, persistent pcpl levels with sustained conversion and release of paclitaxel are observed for the encapsulated prodrug possibly suggesting the formation of a drug reservoir. The overall results indicate the potential of this promising targeted platform for the improved treatment of lung cancer and other EGFR positive tumors.

Spermidine-mediated poly(lactic-<em>co</em>-glycolic acid)&nbsp;nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis

“…The initial study in vivo verified the biodistribution and lung-target characteristics of the NPs. 67,68 As shown in Figure 14A, at 1-3 hours after administration of AKF solution, plasma drug concentration reached maximum. After that, the drug concentration was gradually eliminated and showed no selective accumulation in any tissue.…”

Antibody-Targeted Nanoparticles for Cancer Treatment

“…Targeting EGFR has also shown invivo efficacy in a range of models. For example, in delivery of paclitaxel-loaded polymeric NPs to lung tumours [36], camptothecin loaded porous silica NPs to a range of EGFR over-expressing tumours including glioblastoma [68] and adriamycin encapsulated polymer-lipid NPs to hepatocellular carcinoma [65]. In this final example, there was also evidence suggesting that both the antibody and adriamycin were contributing to the observed cytotoxicity [65].…”

“…Antibody targeting appears to be complementary to passive intratumoural accumulation mediated by EPR [33][34][35]. Ab-NPs also show improved efficacy and cytotoxicity compared with nontargeted NPs [36]. …”

Polymer-drug conjugates as inhalable drug delivery systems: A review

“…However, the majority of studies on PLGA as pulmonary carrier have focused on encapsulation/adsorption of drugs, proteins, and peptides into PLGA nanoparticle structures, rather than by direct conjugation of drugs onto PLGA [104]. PLGA can be modified to contain cell targeting moieties, but it has a limited availability of favourable functional groups for chemical conjugation [105].…”