BmK CT-modified Multifunctional Dendrimers Labeled With ¹³¹I For Targeted Diagnosis And Therapy Of Gliomas

Early diagnosis and effective therapy of gliomas remainly are tremendous clinical challenges.Current glioma treatments include surgery,radiation therapy,and chemotherapy,but these fail to significantly improve the cure and survival rates of glioma patients.In recent years,nanotechnology has revolutionized tumor therapy with extensive prospects for clinical applications.Nanotechnology can not only provide precise tumor imaging information for surgical excision,but also develop novel platforms for tumor therapy.Importantly,some researchers have developed novel theranostic nanoplatforms that combine the diagnostic and therapeutic functions for cancer treatment.Poly?amidoamine??PAMAM?dendrimers have emerged as an ideal nano-delivery system in cancer imaging and therapy,acting with notable advantage in high chemical stability,biocompatibility,and high affinity to biomolecules.The surface functional groups of PAMAM dendrimers are abundant and are easily conjugated simultaneously with specific ligands,imaging agents and therapeutic materials.Therefore,PAMAM dendrimers have the potential to be exploited as a multifunctional nanoplatform for simultaneous targeting,imaging and therapy of gliomas.Besides,visualization with ¹³¹I is useful for simultaneous SPECT imaging and radiotherapy,but free ¹³¹I localizes minimally to tumors due to typical thyroid iodine absorption.Thus,G5.NH₂ was selected as an appropriate delivery system and BmK CT as a targeting ligand to specifically deliver ¹³¹I to the tumor site.There are three obvious advantages of the nanoparticle:?1?the encapsulation ability of PAMAM is very high and it is very easy to be modified;?2?the ligand BmK CT has high affinity and specificity to glioma;?3?¹³¹I can be used for nuclear imaging and radiotherapy at the same time.The Buthus martensii Karsch chlorotoxin?BmK CT?is a CTX-like peptide which is derived from the venom gland of Buthus martensii Karsch and BmK CT has been reported to act as a novel ligand for MMP-2,inhibiting the enzymatic activity,selectively binding to and slowing the growth of glioma cells.The bioconjugates of BmK CT with other molecules have played an increasing role in diagnostic imaging and treatment of gliomas.The first part summarizes the recent advances in the applications of CTX or BmK CT bioconjugates for glioma-targeted diagnosis and treatment.In addition,recent studies on PAMAM,radionuclide ¹³¹I and CTX or BmK CT bioconjugates also be reported.Finally,the content and innovation of this study have been described.In the second part,G5.NHAc-HPAO-?PEG-BmK CT?-?mPEG?nanoplatform was synthesized and characterized.The G5.NHAc-HPAO-?PEG-CTX?-?mPEG?and G5.NHAc-HPAO-?PEG-MAL?-?mPEG?dendrimers were radiolabeled with ¹³¹I using the chloramine-T method.Through CCK-8,flow cytometry,confocal microscopy and in vitro SPECT imaging,the cytotoxicity,targeting capability and cellular uptake of G5.NHAc-HPAO-?PEG-BmK CT?-?mPEG?and ¹³¹I-G5.NHAc-HPAO-?PEG-BmK CT?-?mPEG?dendrimers were evaluated.It suggests that the G5.NHAc-HPAO-?PEG-BmK CT?-?mPEG?and G5.NHAc-HPAO-?PEG-MAL?-?mPEG?dendrimers do not have cytotoxic effects both in RLE-6TN normal cells and C6 glioma cells.¹³¹I-G5.NHAc-HPAO-?PEG-BmK CT?-?mPEG?dendrimer is radiochemically pure and radiostable in PBS or FBS solution for 24 h.BmK CT-modification could promote inhibitory effects of ¹³¹I-G5.NHAc-HPAO-?PEG-BmK CT?-?mPEG?dendrimer due to increased cellular uptake of ¹³¹I.The G5.NHAc-FI-HPAO-?PEG-BmK CT?-?mPEG?dendrimer is able to targeted binding to C6 cells.The BmK CT-modification enhances the uptake of G5dendrimers and ¹³¹I-labeled dendrimers in the C6 glioma cells.In the third part,biodistribution and radiotherapy efficiency of the ¹³¹I-G5.NHAc-HPAO-?PEG-BmK CT?-?mPEG?dendrimer were evaluated in subcutaneous xenograft glioma bearing nude mice.SPECT imaging was utilized to examine the biodistribution of ¹³¹I-G5.NHAc-HPAO-?PEG-BmK CT?-?mPEG?dendrimer in a nude mouse model.The solution of ¹³¹I-G5.NHAc-HPAO-?PEG-BmK CT?-?mPEG?dendrimer was intravenously injected into mouse via the tail vein.H&E and TUNEL staining were carried out for evaluating the apoptosis of tumor tissue.When compared with the unmodified dendrimers,the BmK CT-modified dendrimer exhibited greater tumor targeted binding in vivo.This indicates that BmK CT-modification is able to enhanced the dendrimer targeting and accumulation in the tumor.Moreover,BmK CT-modification improves the survial rate of the tumor-bearing mice treated with the dendrimers.In sum,BmK CT-modification promotes radiotherapeutic efficacy of the¹³¹I-G5.NHAc-HPAO-?PEG-BmK CT?-?mPEG?dendrimer due to selective binding with glioma cells.The multifunctional dendrimers(both unlabeled and labeled with ¹³¹I labeling)do not cause toxicity in vivo.