Macrophages hold great potential in cancer drug delivery because they can sense chemotactic cues and home to tumors with high efficiency. However, it remains a challenge to load large amounts of therapeutics into macrophages without compromising cell functions. Here we report a silica-based drug nanocapsule approach to solve this issue. Our nanocapsule consists of a drug-silica complex filling and a solid silica sheath, and it is designed to minimally release drug molecules in the early hours of cell entry. While taken up by macrophages at high rates, the nanocapsules minimally affect cell migration in the first 6–12 h, buying time for macrophages to home to tumors and release drugs in situ. In particular, we show that doxorubicin (Dox) as a representative drug can be loaded into macrophages up to 16.6 pg/cell using this approach. When tested in a U87MG xenograft model, intravenously (i.v.) injected Dox-laden macrophages show comparable tumor accumulation as untreated macrophages. Therapy leads to efficient tumor growth suppression, while causing little systematic toxicity. Our study suggests a new cell platform for selective drug delivery, which can be readily extended to the treatment of other types of diseases.
Radiotherapy
remains a major treatment modality for cancer types
such as non-small cell lung carcinoma (or NSCLC). To enhance treatment
efficacy at a given radiation dose, radiosensitizers are often used
during radiotherapy. Herein, we report a nanoparticle agent that can
selectively sensitize cancer cells to radiotherapy. Specifically,
we nitrosylated maytansinoid DM1 and then loaded the resulting prodrug,
DM1-NO, onto poly(lactide-co-glycolic)-block-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles.
The toxicity of DM1 is suppressed by nanoparticle encapsulation and
nitrosylation, allowing the drug to be delivered to tumors through
the enhanced permeability and retention effect. Under irradiation
to tumors, the oxidative stress is elevated, leading to the cleavage
of the S–N bond and the release of DM1 and nitric oxide (NO).
DM1 inhibits microtubule polymerization and enriches cells at the
G2/M phase, which is more radiosensitive. NO under irradiation forms
highly toxic radicals such as peroxynitrites, which also contribute
to tumor suppression. The two components work synergistically to enhance
radiotherapy outcomes, which was confirmed in vitro by clonogenic assays and in vivo with H1299 tumor-bearing
mice. Our studies suggest the great promise of DM1-NO PLGA nanoparticles
in enhancing radiotherapy against NSCLC and potentially other tumor
types.
Background
Recently, gadolinium-intercalated carbon dots (Gd@C-dots) have demonstrated potential advantages over traditional high-Z nanoparticles (HZNPs) as radiosensitizers due to their high stability, minimal metal leakage, and remarkable efficacy.
Results
In this work, two Gd@C-dots formulations were fabricated which bore carboxylic acid (CA-Gd@C-dots) or amino group (pPD-Gd@C-dots), respectively, on the carbon shell. While it is critical to develop innovative nanomateirals for cancer therapy, determining their tumor accumulation and retention is equally important. Therefore, in vivo positron emission tomography (PET) was performed, which found that 64Cu-labeled pPD-Gd@C-dots demonstrated significantly improved tumor retention (up to 48 h post injection) compared with CA-Gd@C-dots. Indeed, cell uptake of 64Cu-pPD-Gd@C-dots reached close to 60% of total dose compared with ~ 5% of 64Cu-CA-Gd@C-dots. pPD-Gd@C-dots was therefore further evaluated as a new radiosensitizer for non-small cell lung cancer treatment. While single dose radiation plus intratumorally injected pPD-Gd@C-dots did lead to improved tumor suppression, the inhibition effect was further improved with two doses of radiation. The persistent retention of pPD-Gd@C-dots in tumor region eliminates the need of reinjecting radiosensitizer for the second radiation.
Conclusions
PET offers a simple and straightforward way to study nanoparticle retention in vivo, and the selected pPD-Gd@C-dots hold great potential as an effective radiosensitizer.
Graphic abstract
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