iRGD-Decorated Polymeric Nanoparticles for the Efficient Delivery of Vandetanib to Hepatocellular Carcinoma: Preparation and in Vitro and in Vivo Evaluation

Abstract

Molecularly targeted agents that are designed to target specific lesions have been proven effective as clinical cancer therapies; however, most currently available therapeutic agents are poorly water-soluble and require oral administration, thereby resulting in low bioavailability and a high risk of side effects due to dose intensification. The rational engineering of systemically injectable medicines that encapsulate such therapeutic payloads may revolutionize anticancer therapies and remains an under-explored area of drug development. Here, the injectable delivery of a nanomedicine complexed with an oral multitargeted kinase inhibitor, vandetanib (vanib), was explored using polymeric nanoparticles (NPs) to achieve the selective accumulation of drug payloads within tumor lesions. To demonstrate this concept, we used biodegradable amphiphilic block copolymer poly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG-PLA) to nanoprecipitate this potent agent to form water-soluble NPs that are suitable for intravenous administration. NP-vanib induced cytotoxic activity by inhibiting the angiogenetic events mediated by VEGFR and EGFR kinases in tested cancer cells and inhibited the growth, tube formation and metastasis of HUVECs. The intravenously injection of NP-vanib into mice bearing HCC BEL-7402 xenografts more effectively inhibited the tumor than the oral administration of vanib. In addition, due to the modular design of these NPs, the drug-loaded particles can easily be decorated with iRGD, a tumor-homing and -penetrating peptide motif, which further improved the in vivo performance of these vanib-loaded NPs. Our results demonstrate that reformulating targeted therapeutic agents in NPs permits their systemic administration and thus significantly improves the potency of currently available, orally delivered agents.

Inhibition of Kupffer Cell Autophagy Abrogates Nanoparticle‐Induced Liver Injury

“…An interesting observation is that many nanomaterials preferentially accumulate in the liver . While this feature has been exploited for designing nanomaterials that specifically target liver and treat liver disease such as liver fibrosis, hepatocellular carcinoma, and viral hepatitis, it also raises the issue of liver toxicity. Indeed, previous studies have reported that a variety of nanoparticles, such as SiO 2 , TiO 2 , Ag, GO, UCP, CdSe/ZnS core–shell quantum dots, Poly‐amidoamine (PAMAM) dendrimers, and so on, induced hepatic injury .…”

Peptide Self-Assembled Nanostructures for Drug Delivery Applications

“…For example, one functional nanostructure could be selfassembled with many different targeting peptides and drugs with multiple purposes. The supramolecular nanoparticles self-assembled with specific targeting motifs including cancer cells and nucleolus have been developed for targeted drug delivery in tumor therapy and gene therapy [136,137]. The functional peptides with lots of arginines could be used to bind with RNA sites for condensed siRNA for the targeted gene drug delivery applications in this system.…”

Targeted drug delivery using iRGD peptide for solid cancer treatment

“…A detail summary of studies of iRGD conjugated nanocarrier was summarized in Table 1. Depending on the chemical composition, the conjugation reaction frequently involves the use of maleimide-thiol reaction 17,31–36,38,40–42,44–46,50,52,54 , Michael addition of acryloyl-amine reaction 39 , alkyne-azide click reaction 49,51 or amidation of carboxyl-amine reaction 43,53 , as demonstrated in Fig. 3.…”

“…Similar successes were demonstrated by conjugating iRGD on doxorubicin/sorafenib lipid-polymer hybrid nanoparticle or anti-angiogenesis agent vandetanib laden PEG-PLGA nanoparticle, which were tested in HepG2 liver cancer or BEL-7402 liver cancer, respectively. 41,42 Moreover, the iRGD conjugated particle was also robustly tested in gene delivery system in different cancer types, such as lung and prostate cancers. 38,39,43 One example was to use iRGD modification to improve the systemic delivery of siRNA that target survivin.…”