Given
the physically encapsulated payloads with drug burst release
and/or low drug loading, it is critical to initiate an innovative
prodrug strategy to optimize the design of modular nanomedicines.
Here, we designed modular pH-sensitive acetone-based ketal-linked prodrugs of dexamethasone (AKP-dexs) and formulated them as nanoparticles.
We comprehensively studied the relationships between AKP-dex structure
and properties, and we selected two types of AKP-dex-loaded nanoparticles
for in vivo studies on the basis of their size, drug loading, and
colloidal stability. In a collagen-induced arthritis rat model, these
AKP-dex-loaded nanoparticles showed higher accumulation in inflamed
joints and better therapeutic efficacy than free dexamethasone phosphate
with less-severe side effects. AKP-dex-loaded nanoparticles may be
useful for treating other inflammatory diseases and thus have great
translational potential. Our findings represent an important step
toward the development of practical applications for acetone-based
ketal-linked prodrugs and are useful in the design of modular nanomedicines.
Emerging clustered regularly interspaced short palindromic repeat/associated protein (CRISPR/Cas) genome editing technology shows great potential in gene therapy. However, proteins and nucleic acids suffer from enzymatic degradation in the physiological environment and low permeability into cells. Exploiting carriers to protect the CRISPR system from degradation, enhance its targeting of specific tissues and cells, and reduce its immunogenicity is essential to stimulate its clinical applications. Here, the authors review the state-of-the-art CRISPR delivery systems and their applications, and describe strategies to improve the safety and efficacy of CRISPR mediated genome editing, categorized by three types of cargo formats, that is, Cas: single-guide RNA ribonucleoprotein, Cas mRNA and single-guide RNA, and Cas plasmid expressing CRISPR/Cas systems. The authors hope this review will help develop safe and efficient nanomaterial-based carriers for CRISPR tools.
Isopropenyl ethers are critical intermediates for accessing medicinally valuable ketal-based prodrugs and biomaterials, but traditional approaches for the synthesis of isopropenyl ethers suffer from poor functional group compatibility and harsh reaction conditions. Here, we develop an organocatalytic transisopropenylation approach to solve these challenges, enabling the synthesis of isopropenyl ethers from various hydroxyl-group-containing small-molecule drugs, polymers, and functional building blocks. The method provides a straightforward and versatile synthesis of isopropenyl ethers, features excellent tolerance of diverse functional groups, applies to a wide range of substrates, and allows scalable synthesis. The development of this organocatalytic transisopropenylation approach enables access to modular preparation of various acid-sensitive ketal-linked prodrugs and functionalized ketalated biomaterials. We expect our syntheses and transformations of isopropenyl ethers will find utility in several diverse fields, including medicinal chemistry, drug delivery, and biomaterials.
Nucleoside
analogue drugs are widely used in cancer therapy and
antiviral therapy, while fast metabolism, drug resistance, and severe
side effects significantly limit their clinical applications. To address
these issues, a variety of ester- and amide-linked prodrugs and their
nanoparticulate formulations have been devised. However, most of these
prodrugs suffer from inefficient transformation to native drugs in
tumor. Here, we report an approach to conjugate gemcitabine, a kind
of anticancer nucleoside drug and widely used to treat cancers, to
polyketal backbone via pH-sensitive ketal linkage, and prepared gemcitabine-containing
polyketal prodrug nanoparticles with minimal drug release under physiological
conditions and acid-triggerable release of native gemcitabine. Intracellular
and intratumoral degradation of the pH-sensitive gemcitabine-containing
polyketal prodrug and incorporation of gemcitabine into DNA were confirmed
by confocal microscopy using EdU, an analogue of gemcitabine. One
single intravenous injection of these gemcitabine-containing polyketal
prodrug nanoparticles demonstrated notable anticancer efficacy in
the A2780 ovarian xenograft tumor model with increased survival rate
and good safety. Our approach can be adopted for other diol nucleoside
analogues to synthesize pH-sensitive nucleoside-polyketal prodrugs
for developing anticancer and antiviral formulations.
The desmoplastic stroma imposes a
fatal physical delivery barrier
in pancreatic ductal adenocarcinoma (PDAC) therapy. Deconstructing
the stroma components hence predominates in stroma-targeting approaches,
but conflicting outcomes have sometimes occurred due to the multifaceted
nature of the stroma. Here, we constructed two sub-20-nm nanomedicines
based on a so-called “next-wave” antifibrotic halofuginone
(HF) and the tumoricidal paclitaxel (PTX) for enhanced PDAC chemotherapy.
This was achieved by coassembling methoxy poly(ethylene glycol)-b-poly(caprolactone) with ketal-linked HF- and PTX-derived
prodrugs. HF nanomedicine and PTX nanomedicine had excellent prodrug–nanocarrier
compatibility and exhibited greatly improved pharmacokinetic profiles
and high tumor accumulation. HF nanomedicine pretreatment restored
stromal homeostasis and considerably facilitated the distribution
of PTX nanomedicine and its penetration into carcinoma cells, leading
to positive modulation of the infiltration of cytotoxic T cells and
significant regression of tumor growth in two PDAC models. Our nanomedicine-based
stromal remodeling strategy appears promising for treating desmoplastic
malignancies.
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