Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor

Abstract

To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4) and a chemotherapeutic drug (doxorubicin) and conjugate with targeting molecules (iRGD peptide) for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors.

Targeted drug delivery using iRGD peptide for solid cancer treatment

“…The effectiveness of iRGD-conjugated nanocarriers has been demonstrated in multiple cases that involve a variety of nanoformulations such as liposomes 31–36 , polymer nanoparticles 37–43 , polymer nanogels 44 , polymersomes 45 , nanocapsules 46 , exosomes 47 , protein nanoparticles 48 , and inorganic nanoparticles (e.g., iron oxide nanoworms, porous silicon nanoparticles and mesoporous silica nanoparticles) 49–53 . A detail summary of studies of iRGD conjugated nanocarrier was summarized in Table 1.…”

“…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.…”

“…49–53 Please note that in certain stroma-rich cancer type, such as a Kras-mutated orthotopic pancreatic cancer model, the iRGD conjugation effect is not less prominent compared to other cancer types. 30 Our interpretation is that in addition to the impenetrable pancreatic tumor stroma, the NRP-1 receptor abundance at the tumor vascular site may be the bottle neck that limits the access of conjugated particles to pass through at the tumor site (see section 2.3).…”

Design and Modification of Anticancer Peptides

“…Then it can be proteolytically cleaved to expose the CRGDK/R sequence on the C-terminal, named C-end Rule (CendR) motif (R/KXXR/K), which has the high affinity to the receptor of neuropilin-1 (NRP-1) and triggers tissue penetration [70]. iRGD has been extensively used as a targeting delivery and penetration tools for nanoparticles [71], peptides [72], monoclonal antibody [73], etc., by chemical conjugated or co-administration [70]. iRGD is one of the most widely used THPs to modify many kind of ACPs, like apoptotic peptide D (KLA) 2 , ATAP, CDD, Thymopentin, TP5, etc.…”

Apoferritin as an ubiquitous nanocarrier with excellent shelf life

“…12 The consequences of this toxicity can be apparent immediately after administration of the drug, but they can also take many years to manifest. 13 Dox causes the formation of reactive oxygen species, and iron oxidation induces a release of cytochrome C from mitochondria, leading to apoptosis.…”