Achieving spatiotemporal control of molecular self-assembly associated with actuation of biological functions inside living cells remains a challenge owing to the complexity of the cellular environments and the lack of characterization tools. We present, for the first time, the organelle-localized self-assembly of a peptide amphiphile as a powerful strategy for controlling cellular fate. A phenylalanine dipeptide (FF) with a mitochondria-targeting moiety, triphenyl phosphonium (Mito-FF), preferentially accumulates inside mitochondria and reaches the critical aggregation concentration to form a fibrous nanostructure, which is monitored by confocal laser scanning microscopy and transmission electron microscopy. The Mito-FF fibrils induce mitochondrial dysfunction via membrane disruption to cause apoptosis. The organelle-specific supramolecular system provides a new opportunity for therapeutics and in-depth investigations of cellular functions.
Hyaluronic acid (HA) has been widely investigated in cancer therapy due to its excellent characteristics. HA, which is a linear anionic polymer, has biocompatibility, biodegradability, non-immunogenicity, non-inflammatory, and non-toxicity properties. Various HA nanomedicines (i.e., micelles, nanogels, and nanoparticles) can be prepared easily using assembly and modification of its functional groups such as carboxy, hydroxy and N-acetyl groups. Nanometer-sized HA nanomedicines can selectively deliver drugs or other molecules into tumor sites via their enhanced permeability and retention (EPR) effect. In addition, HA can interact with overexpressed receptors in cancer cells such as cluster determinant 44 (CD44) and receptor for HA-mediated motility (RHAMM) and be degraded by a family of enzymes called hyaluronidase (HAdase) to release drugs or molecules. By interaction with receptors or degradation by enzymes inside cancer cells, HA nanomedicines allow enhanced targeting cancer therapy. In this article, recent studies about HA nanomedicines in drug delivery systems, photothermal therapy, photodynamic therapy, diagnostics (because of the high biocompatibility), colloidal stability, and cancer targeting are reviewed for strategies using micelles, nanogels, and inorganic nanoparticles.
Systemic
administration of mesoporous silica nanoparticles (MSNs)
in biomedical applications has recently been questioned because of
poor degradability, which is necessary for the successful development
of new drug-delivery systems. Herein, we report the development of
colloidal-state-degradable MSNs functionalized with versatile polymer-gatekeepers
with a cancer-cell-targeted moiety. The polymer MSNs (PMSNs) were
designed with disulfide cross-linking enabling safe encapsulation
until cargos are delivered to target cancer cells. Selective targeting
was achieved by decoration of CD44-receptor-targeting ligands, hyaluronic
acid (HA), with HA-PMSNs. The selective cellular uptake mechanism
of the fabricated targeted nanocarrier into CD44-overexpressed cancer
cells was demonstrated through the clathrin- and macropinocytosis-mediated
pathways. Upon internalization into cancer cells, doxorubicin loaded
into the HA-PMSNs can be released by degradation of the polymer shells
in the reducing intracellular microenvironment that consequentially
induces cell death and further degradation of the MSNs. This study
offers a simple technique to fabricate a versatile drug carrier with
a high drug loading capacity.
Current drug delivery systems are hampered by poor delivery to tumors, in part reflecting poor encapsulation stability of nanocarriers. Although nanocarriers such as polymeric micelles have high colloidal stability and do not aggregate or precipitate in bulk solution, nanocarriers with low encapsulation stability can lose their cargo during circulation in blood due to interactions with blood cells, cellular membranes, serum proteins, and other biomacromolecules. The resulting premature drug release from carriers limits the therapeutic efficacy at target sites. Herein, we report a simple and robust technique to improve encapsulation stability of drug delivery systems. Specifically, we show that installation of disulfide cross-linked noncovalent polymer gatekeepers onto mesoporous silica nanoparticles with a high loading capacity for hydrophobic drugs enhances in vivo therapeutic efficacy by preventing premature release of cargo. Subsequent release of drug cargos was triggered by cleavage of disulfide cross-linking by glutathione, leading to improved antitumor activity of doxoroubicin in mice. These findings provide novel insights into the development of nanocarriers with high encapsulation stability and improved in vivo therapeutic efficacy.
A simple peptide based prodrug of camptothecin (CPT) has been synthesised in which the CPT is conjugated to a tripeptide (KCK) via a disulfide linkage (KCK-CPT) and self-assembled into well-defined nanostructures in water depending on the concentration. The hyaluronic acid (HA) complex of KCK-CPT exhibited target specific toxicity with excellent antitumour efficiency.
The
intracellular or pericellular self-assembly of amphiphilic
peptides is emerging as a potent cancer therapeutic strategy. Achieving
the self-assembly of amphiphilic peptides inside a cell or cellular
organelle is challenging due to the complex cellular environment,
which consists of many amphiphilic biomolecules that may alter the
self-assembling propensity of the synthetic peptides. Herein, we show
that the hydrophobic–hydrophilic balance of the amphiphilic
peptides determines the self-assembling propensity, thereby controlling
the fate of the cell. A series of peptides were designed to target
and self-assemble inside the mitochondria of cancer cells. The hydrophobicity
of the peptides was tuned by varying their N-terminus capping. The
analysis showed that the largest hydrophobic peptide was self-assembled
before reaching the mitochondria and showed no selectivity toward
cancer cells, whereas hydrophilic peptides could not self-assemble
inside the mitochondria. Optimum balance between hydrophobicity and
hydrophilicity is a critical factor for achieving self-assembly inside
the mitochondria, thereby providing greater selectivity against cancer
cells.
Mitochondria are essential intracellular organelles involved in many cellular processes, especially adenosine triphosphate (ATP) production. Since cancer cells require high ATP levels for proliferation, ATP elimination can be a unique...
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