Polymeric micellar drug carriers have emerged as effective tools to enhance the solubility and bioavailability of hydrophobic drugs. These micelles possess a nano size structure that facilitates their passive targeting in human tissues through their enhanced permeability and retention (EPR) effect. However, there is a growing need for active targeting strategies that can direct the micelles to specific sites within the body. In this review, we will explore recent advancements in endogenous targeted delivery strategies using micelles as a delivery system for pharmaceutical ingredients. One approach discussed here is the use of physical and chemical conjugates, which involve the binding of targeting moieties to specific tissues through physical or covalent interactions. Another strategy involves the use of responsive moieties that can release drugs upon internal stimuli at the targeted sites. Ligands, including small molecules, natural polymers, and proteins/peptides, which exhibit high affinities to specific receptors present in the target tissues, are also explored as targeting moieties in micellar drug delivery. Lastly, various approaches for improving therapeutic effects are investigated to evade immune clearance and integrate the micelles into the targeted tissues. Various combined targeting approaches along with the limitations of individual strategies for achieving improved targeting efficiency are discussed. In summary, this review highlights various recent strategies for achieving targeted drug delivery using polymeric micellar carriers to improve efficacy and specificity, ultimately enhancing the therapeutic outcomes for patients. 

Rational design of polymeric micelles for targeted therapeutic delivery

Camptothecin (CPT) is a potent anti-cancer agent targeting topoisomerase I (TOP1). However, CPT has poor pharmacokinetic properties, causes toxicities, and leads to drug resistance, which limit its clinical use. In this paper, to review the current state of CPT research. We first briefly explain CPT's TOP1 inhibition mechanism and the key hurdles in CPT drug development. Then we examine strategies to overcome CPT's limitations through structural modifications and advanced delivery systems. Though modifications alone seem insufficient to fully enhance CPT's therapeutic potential, structure-activity relationship analysis provides insights to guide optimization of CPT analogs. In comparison, advanced delivery systems integrating controlled release, imaging capabilities, and combination therapies via stimulus-responsive linkers and targeting moieties show great promise for improving CPT's pharmacological profile. Looking forward, multifaceted approaches combining selective CPT derivatives with advanced delivery systems, informed by emerging biological insights, hold promise for fully unleashing CPT's anti-cancer potential. 

Unleashing the Potential of Camptothecin: Exploring Innovative Strategies for Structural Modification and Therapeutic Advancements

Many of the utilized drugs which already exist in the pharmaceutical sector are hydrophobic in nature. 

Advances in active targeting of ligand-directed polymeric nanomicelles via exploiting overexpressed cellular receptors for precise nanomedicine

Liver cirrhosis is the end-stage of chronic liver disease, characterized by inflammation, necrosis, advanced fibrosis, and regenerative nodule formation. Long-term inflammation can cause continuous damage to liver tissues and hepatocytes, along with increased vascular tone and portal hypertension. Among them, fibrosis is the necessary stage and essential feature of liver cirrhosis, and effective antifibrosis strategies are commonly considered the key to treating liver cirrhosis. Although different therapeutic strategies aimed at reversing or preventing fibrosis have been developed, the effects have not be more satisfactory. In this review, we discussed abnormal changes in the liver microenvironment that contribute to the progression of liver cirrhosis and highlighted the importance of recent therapeutic strategies, including lifestyle improvement, small molecular agents, traditional Chinese medicine, stem cells, extracellular vesicles, and gut remediation, that regulate liver fibrosis and liver cirrhosis. Meanwhile, therapeutic strategies for nanoparticles are discussed, as are their possible underlying broad application and prospects for ameliorating liver cirrhosis. Finally, we also reviewed the major challenges and opportunities of nanomedicine‒biological environment interactions. We hope this review will provide insights into the pathogenesis and molecular mechanisms of liver cirrhosis, thus facilitating new methods, drug discovery, and better treatment of liver cirrhosis. 

Liver cirrhosis: molecular mechanisms and therapeutic interventions

Liver fibrosis is characterized by excessive extracellular matrix (ECM) deposition triggered by hepatic stellate cells (HSCs). As central players in fibrosis progression, HSCs are the most important therapeutic targets for antifibrotic therapy. However, owing to the limitations of systemic drug administration, there is still no suitable and effective clinical treatment. In recent years, nanosystems have demonstrated expansive therapeutic potential and evolved into a clinical modality. In liver fibrosis, nanosystems have undergone a paradigm shift from targeting the whole liver to locally targeted modifying processes. Nanomedicine delivered to HSCs has significant potential in managing liver fibrosis, where optimal management would benefit from targeted delivery, personalized therapy based on the specific site of interest, and minor side effects. In this review, we present a brief overview of the role of HSCs in the pathogenesis of liver fibrosis, summarize the different types of nanocarriers and their specific delivery applications in liver fibrosis, and highlight the biological barriers associated with the use of nanosystems to target HSCs and approaches available to solve this issue. We further discuss in-depth all the molecular target receptors overexpressed during HSC activation in liver fibrosis and their corresponding ligands that have been used for drug or gene delivery targeting HSCs. 

Nano-encapsulation of drugs to target hepatic stellate cells: Toward precision treatments of liver fibrosis

As the central cellular player in fibrogenesis, activated hepatic stellate cells (aHSCs) are the major target of antifibrotic nanomedicines. Based on our finding that activated HSCs increase the expression of folate receptor alpha (FRα), we tried to apply folic acid (FA) decoration to generate an active drug-targeting at aHSCs and suppress hepato-fibrogenesis. FA-conjugated poly(ethylene glycol)-poly(ε-caprolactone) copolymers (PEG-PCL) were synthesized and self-assembled into the spherical micelles that owned a uniform size distribution averaging at 60 nm, excellent hemo- and cyto-compatibility, and pH-sensitive stability. These FA-modified micelles were preferentially ingested by aHSCs as expected and accumulated more in acutely CCl4 injured mouse livers compared to nondecorated counterparts. Such an aHSC targetability facilitated the loaded medicinal camptothecin (CPT) to achieve a greater therapeutic efficacy and inhibition of MF phenotypic genes in aHSCs. Encouragingly, though free CPT and nontargeting CPT micelles produced negligible curative outcomes, FA-decorated CPT micelles yielded effectively remedial effects in chronically CCl4-induced fibrotic mice, as represented by a significant shrinkage of aHSC population, suppression of fibrogenesis, and recovery of liver structure and function, clearly indicating the success of the folate decoration-supported aHSC-targeted strategy for antifibrotic nanomedicines in fibrosis resolution.

Folate Decoration Supports the Targeting of Camptothecin Micelles against Activated Hepatic Stellate Cells and the Suppression of Fibrogenesis.

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Folate Decoration Supports the Targeting of Camptothecin Micelles against Activated Hepatic Stellate Cells and the Suppression of Fibrogenesis.