Nanoencapsulation of ABT-737 and camptothecin enhances their clinical potential through synergistic antitumor effects and reduction of systemic toxicity

Abstract

The simultaneous delivery of multiple cancer drugs in combination therapies to achieve optimal therapeutic effects in patients can be challenging. This study investigated whether co-encapsulation of the BH3-mimetic ABT-737 and the topoisomerase I inhibitor camptothecin (CPT) in PEGylated polymeric nanoparticles (NPs) was a viable strategy for overcoming their clinical limitations and to deliver both compounds at optimal ratios. We found that thrombocytopenia induced by exposure to ABT-737 was diminished through its encapsulation in NPs. Similarly, CPT-associated leukopenia and gastrointestinal toxicity were reduced compared with the administration of free CPT. In addition to the reduction of dose-limiting side effects, the co-encapsulation of both anticancer compounds in a single NP produced synergistic induction of apoptosis in both in vitro and in vivo colorectal cancer models. This strategy may widen the therapeutic window of these and other drugs and may enhance the clinical efficacy of synergistic drug combinations.

Antagonism of Bcl-XL is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells

“…A therapeutic window may be found by careful dose escalation studies, Alternatively, novel strategies may be necessary to minimize this adverse effect. For example, encapsulation of ABT-737 in nanoparticles has been shown to enhance its anti-tumour effects while minimizing thrombocytopenia [ 31 ]. Alternatively, we have shown more than additive effects when paclitaxel, which is known to have “platelet sparing” properties, is combined with navitoclax and carboplatin [ 15 ].…”

Sulforaphane promotes immune responses in a WEHI-3-induced leukemia mouse model through enhanced phagocytosis of macrophages and natural killer cell activities in vivo

“…In order to protect against invading foreign antigens, numerous white blood cells interact to produce immune responses in humans (1). Clinically, numerous plant-derived bioactive compounds have been used to treat patients with cancer, including paclitaxel from Taxus brevifolia and camptothectin from Camptotheca acuminata (21)(22)(23)(24). A previous study demonstrated that SFN induces cell cycle arrest and induces apoptosis, suggesting that it may be a novel therapeutic against leukemia malignancies (17).…”

Development of an advanced nanoformulation for the intracellular delivery of a caspase-3 selective activity-based probe

“…Next the encapsulation of the CS1 probe into PEG-PLGA nanoparticles through a single emulsion solvent evaporation (SESE) technique was undertaken. This methodology, previously optimised within our laboratory, (36) allows for the encapsulation of hydrophobic molecules into PLGA-based nanoparticle. The chosen nanoformulation was composed of a 75 % of PLGA and 25 % of mPEG-PLGA (polymer ratio 1:2, AK010).…”

“…(37,38) This formulation gives nanoparticles in which the amount of PEG on the surface is roughly 8.25 %, amount that we have previously shown be ideal to ensure stealth nanoparticles, quantified by nanoparticle uptake by a murine macrophage cell line (Raw 264.7). (36) Following formation of CS1-NP and blank nanoparticles (BNP), characterisation studies were carried out through dynamic light scattering (DLS) analysis and results are summarised in table 1. The resulting particles are all in the size range of interest (~200 nm), with CS1-NP being approximately 10 nm bigger than BNP due to loading cargo.…”

“…To address this problem, we sought to develop PLGA-based nanoparticles for the encapsulation of CS1 within the polymeric core, similarly to work previously conducted by our group for in vivo delivery of drugs in the cancer therapy. (36,50) In addition, the hydrolysis that PLGA undertakes in water results in the release of the encapsulated agent over time, allowing for its accumulation in the cytoplasmic compartment. (51) Furthermore, the entrapment of the ABP within the nanoparticle combined with the rapid endosomal escape that PEG-PLGA nanoparticles normally undertake, (41) results in extra protection of the ABP from labelling lysosomal proteases.…”