Inhibition of C6 glioma in vivo by combination chemotherapy of implantation of polymer wafer and intracarotid perfusion of transferrin-decorated nanoparticles

Abstract

Abstract. The objective of this study was to develop a combination chemotherapy of implantation of a 3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-loaded wafer and intracarotid perfusion of BCNU-loaded nanoparticles for glioma treatment in vivo. BCNU-loaded poly(D,L-lactic acid) (PLA) nanoparticles coated with transferrin (Tf) were prepared by a solvent evaporation/diffusion method using Tf as the emulsifier. X-ray photoelectron spectroscopy, BrattonMarshall colorimetric assay and zeta-potential analysis confirmed the existence of Tf on the nanoparticles and their functional activities. BCNU-loaded PLA wafers were made of BCNU-loaded PLA microspheres. In vitro drug release behavior demonstrated that BCNU was released from the Tf-PLA nanoparticles and wafers in two distinct phases. The biodistribution of Tf-coated nanoparticles investigated by 99m Tc-labeled single-photon emission computed tomography (SPECT) showed that the surface-containing Tf-PLA nanoparticles were concentrated in the brain. Inhibition of tumor growth in the C6 glioma-bearing animal model showed that combinational chemotherapy of BCNU-loaded wafer and BCNU-loaded PLA nanoparticles had a stronger inhibitory effect and prolonged the average survival time of rats (164%) compared with that of the control group. Furthermore, the tumors of this treatment group were not visible by examination at 4 weeks. The results of this study demonstrate for the first time that combination therapy of implantation of a BCNUloaded wafer and intracarotid perfusion of BCNU-loaded nanoparticles may be a new strategy for glioma gene therapy.

Crossing the Blood-Brain Barrier: Advances in Nanoparticle Technology for Drug Delivery in Neuro-Oncology

“…The use of polymeric NPs to improve chemotherapeutic access to brain tumors has been extensively explored. PLA nanoparticles coated with Tf and loaded with the anticancer agent 3-bis(2-chloroethyl)-1-nitrosourea have been shown to significantly improve survival in a rat glioma model [130,131]. Additionally, doxorubicin bound to PBCA accumulates in the rat brain after intravenous administration at greater concentrations than seen with administration of doxorubicin alone, and results in less cardiotoxicity and cytotoxicity [132,133].…”

Nanoparticle Targeting with Antibodies in the Central Nervous System

“…Anti-TfR-conjugated poly(lactic acid) NPs [ 124 , 125 ], PEG–poly(lactic acid) NPs [ 126 ], dendrimers [ 127 ], gold NPs [ 116 ], mesoporous silica NPs [ 128 ], liposomes [ 129 ], human serum albumin NPs [ 130 ], and QDs [ 131 , 132 ] have been reported to cross the BBB. A variety of methods have been used to confirm successful crossing, such as in vivo imaging (e.g., single-photon emission computed tomography [ 124 ]), analysis of isolated cell populations in the brain (e.g., counting of NPs after harvesting and dissociating brain tissue [ 128 , 129 , 131 ]), in vitro BBB models [ 126 , 127 ], or evaluation of a unique function of the delivered payload effect in vivo (e.g., reduced nociception through opioid agonist delivery [ 130 ]). However, targeting TfR has limitations; TfR expression decreases after administration of bivalent anti-TfR Ab constructs [ 133 – 135 ], while monovalent constructs maintain the same level of expression.…”

“…Incorporating other analytical methods, most convincingly imaging, is important to link effectiveness of the Ab–NP with BBB penetration. The use of complementary imaging methods in vivo is especially compelling, although this often requires the incorporation of other elements that allow for imaging (e.g., fluorophores) into the NP design [ 124 , 125 , 129 ]. These added elements also create opportunities for artifacts (such as through imaging probe detachment) that may make experimental results difficult to interpret [ 153 ].…”

Combining Nanotechnology and Gas Plasma as an Emerging Platform for Cancer Therapy: Mechanism and Therapeutic Implication

“…Polymeric and magnetic NPs coated with anti-HER2 antibodies are used for HER2-receptor-positive cancers, especially ovarian and breast cancer [ 44 , 45 ]. Transferrin-coated liposomes are used against head and neck cancer [ 46 ] and glioblastoma [ 47 ].…”