Direct intracellular delivery of antibodies has gained much attention, although only a few agents have been developed, and none of them has reached clinical stages. The main obstacles here are the insufficient characteristics of delivery systems including stability and appropriate ability for intracellular antibody release. We tailored the structure of polyion complex (PIC) micelles by loading transiently charge-converted antibody derivatives for achieving enhanced stability, delivery to cytosol, and precise antigen recognition inside cells. Citraconic anhydride was used for the charge conversion of the antibody; the optimized degree of modification was identified to balance the stability of PIC micelles in the extracellular compartment and prompt pH-triggered disintegration after their translocation into the acidic endosomal compartment of target cells. The use of a mixture of homo- and block-catiomers in an appropriate ratio to construct PIC micelles substantially enhanced the endosomal escaping efficacy of the loaded antibody, leading to improved recognition of intracellular antigens.
Nanomedicines capable of smart operation at the targeted site have the potential to achieve the utmost therapeutic benefits. Providing nanomedicines that respond to endogenous stimuli with an additional external trigger may improve the spatiotemporal control of their functions, while avoiding drawbacks from their inherent tissue distribution. Herein, by exploiting the permeabilization of endosomes induced by photosensitizer agents upon light irradiation, we complemented the intracellular action of polymeric micelles incorporating camptothecin (CPT), which can sharply release the loaded drug in response to the reductive conditions of the cytosol, as an effective strategy for precisely controlling the function of these nanomedicines in vivo, while advancing toward a light-activated chemotherapy. These camptothecin-loaded micelles (CPT/m) were stable in the bloodstream, with minimal drug release in extracellular conditions, leading to prolonged blood circulation and high accumulation in xenografts of rat urothelial carcinoma. With the induction of endosomal permeabilization with the clinically approved photosensitizer, Photofrin, the CPT/m escaped from the endocytic vesicles of cancer cells into the cytosol, as confirmed both in vitro and in vivo by real-time confocal laser microscopies, accelerating the drug release from the micelles only in the irradiated tissues. This spatiotemporal switch significantly enhanced the in vivo antitumor efficacy of CPT/m without eliciting any toxicity, even at a dose 10-fold higher than the maximum tolerated dose of free CPT. Our results indicate the potential of reduction-sensitive drug-loaded polymeric micelles for developing safe chemotherapies after activation by remote triggers, such as light, which are capable of permeabilizing endosomal compartments.
Boron neutron
capture therapy (BNCT) is a promising radiotherapy
for treating glioblastoma multiforme (GBM). However, the penetration
of drugs (e.g., sodium borocaptate and BSH) for BNCT into brain tumors
is limited by cerebral vesicular protective structures, the blood–brain
barrier, and the blood–brain tumor barrier (BTB). Although
BSH has been reported to be selectively taken up by tumors, it is
rapidly excreted from the body and cannot achieve a high tumor-to-normal
brain ratio (T/N ratio) and tumor-to-blood ratio (T/B ratio). Despite
the development of large-molecular weight boron compounds, such as
polymers and nanoparticles, to enhance the permeation and retention
effect, their effects remain insufficient for clinical use. To improve
the efficiency of boron delivery to the tumor site, we propose combinations
of self-assembled boron-containing polyanion [polyethylene glycol-b-poly((closo-dodecaboranyl)thiomethylstyrene)
(PEG-b-PMBSH)] nanoparticles (295 ± 2.3 nm in
aqueous media) coupled with cationic microbubble (B-MB)-assisted focused
ultrasound (FUS) treatment. Upon FUS sonication (frequency = 1 MHz,
pressure = 0.3–0.7 MPa, duty cycle = 0.5%, sonication = 1 min),
B-MBs can simultaneously achieve safe BTB opening and boron drug delivery
into tumor tissue. Compared with the MBs of the PEG-b-PMBSH mixture group (B + MBs), B-MBs showed 3- and 2.3-fold improvements
in the T/N (4.4 ± 1.4 vs 1.3 ± 0.1) and T/B ratios (1.4
± 0.6 vs 0.1 ± 0.1), respectively, after 4 min of FUS sonication.
The spatial distribution of PEG-b-PMBSH was also
improved by the complex of PEG-b-PMBSH with MBs.
The findings presented herein, in combination with the expanding clinical
application of FUS, may improve BNCT and treatment of GBM.
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