As unique molecules with both therapeutic and diagnostic properties, porphyrin derivatives have been extensively employed for cancer treatment. Porphyrins not only show powerful phototherapeutic ...effects (photodynamic and photothermal therapies), but also exhibit excellent imaging capacities, such as near-infrared fluorescent imaging (NIRFI), magnetic resonance imaging (MRI), photoacoustic imaging (PAI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). In order to take advantage of their robust phototherapeutic effects and excellent imaging capacities, porphyrins can be used to create nanomedicines with effective therapeutic and precise diagnostic properties for cancer treatment. In this Review, we summarize porphyrin-based nanomedicines which have been developed recently, including porphyrin-based liposomes, micelles, polymeric nanoparticles, peptide nanoparticles, and small-molecule nanoassemblies, and their applications on cancer therapy and diagnosis. The outlook and limitation of porphyrin-based nanomedicines are also reviewed.
Human epidermal growth factor receptor 2 (HER2) is overexpressed in >20% of breast cancers. Dimerization of HER2 receptors leads to the activation of downstream signals enabling the proliferation and ...survival of malignant phenotypes. Owing to the high expression levels of HER2, combination therapies are currently required for the treatment of HER2
breast cancer. Here, we designed non-toxic transformable peptides that self-assemble into micelles under aqueous conditions but, on binding to HER2 on cancer cells, transform into nanofibrils that disrupt HER2 dimerization and subsequent downstream signalling events leading to apoptosis of cancer cells. The phase transformation of peptides enables specific HER2 targeting, and inhibition of HER2 dimerization blocks the expression of proliferation and survival genes in the nucleus. We demonstrate, in mouse xenofraft models, that these transformable peptides can be used as a monotherapy in the treatment of HER2
breast cancer.
Nanomedicines are attractive paradigms to deliver drugs, contrast agents, immunomodulators, and gene editors for cancer therapy and diagnosis. However, the currently developed nanomedicine suffers ...from poor serum stability, premature drug release, and lack of responsiveness. Crosslinking strategy can be utilized to overcome these shortcomings by employing stimuli‐responsive chemical bonds to tightly hold the nanostructure and releasing the payloads spatiotemporally in a highly controlled manner. In this Review, we summarize the recently ingenious design of the stimuli‐responsive crosslinked nanomedicines (SCN) in the field of cancer treatment and their advances in circumventing the drawbacks of the conventional drug delivery system. We classify the SCNs into three categories based on the crosslinking strategies, including built‐in, on‐surface, and inter‐particle crosslinking nanomedicines. Thanks to the stimuli‐responsive crosslinkages, SCNs are capable of keeping robust stability during systemic circulation. They also respond to the particular tumoral conditions to experience a series of dynamic changes, such as the changes in size, surface charge, targeting moieties, integrity, and imaging signals. These characteristics allow them to efficiently overcome different biological barriers and substantially improve the drug delivery efficiency, tumor‐targeting ability, and imaging sensitivities. With the examples discussed, we envision that our perspectives can inspire more attempts to engineer intelligent nanomedicine to achieve effective cancer therapy and diagnosis.
We classify the stimuli‐responsive crosslinked nanomedicines (SCNs) into three categories based on the crosslinking strategies, including built‐in, on‐surface, and inter‐particle crosslinking nanomedicines. These SCNs can respond to particular tumoral stimuli and go through a series of dynamic changes to circumvent different biological barriers, and subsequently improve anti‐cancer efficacy and imaging sensitivity and specificity.
Nanotheranostics with integrated diagnostic and therapeutic functions show exciting potentials towards precision nanomedicine. However, targeted delivery of nanotheranostics is hindered by several ...biological barriers. Here, we report the development of a dual size/charge- transformable, Trojan-Horse nanoparticle (pPhD NP) for delivery of ultra-small, full active pharmaceutical ingredients (API) nanotheranostics with integrated dual-modal imaging and trimodal therapeutic functions. pPhD NPs exhibit ideal size and charge for drug transportation. In tumour microenvironment, pPhD NPs responsively transform to full API nanotheranostics with ultra-small size and higher surface charge, which dramatically facilitate the tumour penetration and cell internalisation. pPhD NPs enable visualisation of biodistribution by near-infrared fluorescence imaging, tumour accumulation and therapeutic effect by magnetic resonance imaging. Moreover, the synergistic photothermal-, photodynamic- and chemo-therapies achieve a 100% complete cure rate on both subcutaneous and orthotopic oral cancer models. This nanoplatform with powerful delivery efficiency and versatile theranostic functions shows enormous potentials to improve cancer treatment.
Control-flow attestation (CFA) is a mechanism that securely logs software execution paths running on remote devices. It can detect whether a device is being control-flow hijacked by launching a ...challenge–response process. In the growing landscape of the Internet of Things, more and more peer devices need to communicate to share sensed data and conduct inter-operations without the involvement of a trusted center. Toward the scalability of CFA mechanisms and mitigating the single-point failure, it is important to design a decentralized CFA schema. This paper proposed a decentralized schema (CFRV) to verify the control flow on remote devices. Moreover, it introduces a token (asymmetric secret slices) into peer devices to make the attestation process mutual. In this case, CFRV can mitigate a particular kind of man-in-the-middle attack called response defraud. We built our prototype toolbox on Raspberry-Pi to formulate our proof of concept. In our evaluation, CFRV protects the verification process from malicious verifiers and the man-in-the-middle attack. The proposed mechanism can also limit the PKI (Public Key Infrastructure) usage to a single stage to save the peer devices’ computational cost. Compared to related decentralized schemes, the cryptographic operation’s duration is reduced by 40%.
Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here we propose a self-delivering one-component ...new-chemical-entity nanomedicine (ONN) strategy to improve cancer therapy through incorporation of the self-assembly principle into drug design. A lysosomotropic detergent (MSDH) and an autophagy inhibitor (Lys05) are hybridised to develop bisaminoquinoline derivatives that can intrinsically form nanoassemblies. The selected BAQ12 and BAQ13 ONNs are highly effective in inducing lysosomal disruption, lysosomal dysfunction and autophagy blockade and exhibit 30-fold higher antiproliferative activity than hydroxychloroquine used in clinical trials. These single-drug nanoparticles demonstrate excellent pharmacokinetic and toxicological profiles and dramatic antitumour efficacy in vivo. In addition, they are able to encapsulate and deliver additional drugs to tumour sites and are thus promising agents for autophagy inhibition-based combination therapy. Given their transdisciplinary advantages, these BAQ ONNs have enormous potential to improve cancer therapy.
Abstract To systematically elucidate the effect of surface charge on the cellular uptake and in vivo fate of PEG-oligocholic acid based micellar nanoparticles (NPs), the distal PEG termini of ...monomeric PEG-oligocholic acid dendrimers (telodendrimers) are each derivatized with different number ( n = 0, 1, 3 and 6) of anionic aspartic acids (negative charge) or cationic lysines (positive charge). Under aqueous condition, these telodendrimers self-assemble to form a series of micellar NPs with various surface charges, but with similar particle sizes. NPs with high surface charge, either positive or negative, were taken up more efficiently by RAW 264.7 murine macrophages after opsonization in fresh mouse serum. Mechanistic studies of cellular uptake of NPs indicated that several distinct endocytic pathways (e.g., clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis) were involved in the cellular uptake process. After their cellular uptake, the majority of NPs were found to localize in the lysosome. Positively charged NPs exhibited dose-dependent hemolytic activities and cytotoxicities against RAW 264.7 cells proportional to the positive surface charge densities; whereas negatively charged NPs did not show obvious hemolytic and cytotoxic properties. In vivo biodistribution studies demonstrated that undesirable liver uptake was very high for highly positively or negatively charged NPs, which is likely due to active phagocytosis by macrophages (Kupffer cells) in the liver. In contrast, liver uptake was very low but tumor uptake was very high when the surface charge of NPs was slightly negative. Based on these studies, we can conclude that slightly negative charge may be introduced to the NPs surface to reduce the undesirable clearance by the reticuloendothelial system (RES) such as liver, improve the blood compatibility, thus deliver the anti-cancer drugs more efficiently to the tumor sites.
Abstract
Activation and migration of endogenous mesenchymal stromal cells (MSCs) are critical for bone regeneration. Here, we report a combinational peptide screening strategy for rapid discovery of ...ligands that not only bind strongly to osteogenic progenitor cells (OPCs) but also stimulate osteogenic cell Akt signaling in those OPCs. Two lead compounds are discovered, YLL3 and YLL8, both of which increase osteoprogenitor osteogenic differentiation
in vitro
. When given to normal or osteopenic mice, the compounds increase mineral apposition rate, bone formation, bone mass, and bone strength, as well as expedite fracture repair through stimulated endogenous osteogenesis. When covalently conjugated to alendronate, YLLs acquire an additional function resulting in a “tri-functional” compound that: (i) binds to OPCs, (ii) targets bone, and (iii) induces “pro-survival” signal. These bone-targeted, osteogenic peptides are well suited for current tissue-specific therapeutic paradigms to augment the endogenous osteogenic cells for bone regeneration and the treatment of bone loss.
Distance-dependent magnetic resonance tuning (MRET) technology enables the sensing and quantitative imaging of biological targets in vivo, with the advantage of deep tissue penetration and fewer ...interactions with the surroundings as compared with those of fluorescence-based Förster resonance energy transfer. However, applications of MRET technology in vivo are currently limited by the moderate contrast enhancement and stability of T
-based MRET probes. Here we report a new two-way magnetic resonance tuning (TMRET) nanoprobe with dually activatable T
and T
magnetic resonance signals that is coupled with dual-contrast enhanced subtraction imaging. This integrated platform achieves a substantially improved contrast enhancement with minimal background signal and can be used to quantitatively image molecular targets in tumours and to sensitively detect very small intracranial brain tumours in patient-derived xenograft models. The high tumour-to-normal tissue ratio offered by TMRET in combination with dual-contrast enhanced subtraction imaging provides new opportunities for molecular diagnostics and image-guided biomedical applications.
Multifunctional nanoparticles with combined diagnostic and therapeutic functions show great promise towards personalized nanomedicine. However, attaining consistently high performance of these ...functions in vivo in one single nanoconstruct remains extremely challenging. Here we demonstrate the use of one single polymer to develop a smart 'all-in-one' nanoporphyrin platform that conveniently integrates a broad range of clinically relevant functions. Nanoporphyrins can be used as amplifiable multimodality nanoprobes for near-infrared fluorescence imaging (NIRFI), magnetic resonance imaging (MRI), positron emission tomography (PET) and dual modal PET-MRI. Nanoporphyrins greatly increase the imaging sensitivity for tumour detection through background suppression in blood, as well as preferential accumulation and signal amplification in tumours. Nanoporphyrins also function as multiphase nanotransducers that can efficiently convert light to heat inside tumours for photothermal therapy (PTT), and light to singlet oxygen for photodynamic therapy (PDT). Furthermore, nanoporphyrins act as programmable releasing nanocarriers for targeted delivery of drugs or therapeutic radio-metals into tumours.
PDF
