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Identifying tumor cells can be challenging due to cancer's complex and heterogeneous nature. Here, an efficacious phosphorescent probe that can precisely highlight tumor cells has been created. By combining the ruthenium(II) complex with oligonucleotides, we have developed a nanosized functional ruthenium(II) complex (Ru@DNA) with dimensions ranging from 300 to 500 nm. Our research demonstrates that Ru@DNA can readily traverse biomembranes via ATP-dependent endocytosis without carriers. Notably, the nanosized ruthenium(II) complex exhibits rapid and selective accumulation within tumor cells, possibly attributed to the nanoparticles' enhanced permeation and retention (EPR) effect. Ru@DNA can also effectively discern and label the transplanted cancer cells in the zebrafish model. Moreover, Ru@DNA is efficiently absorbed into the intestine and further distributed in the pancreas. Our findings underscore the potential of Ru@DNA as a DNA-based nanodevice derived from a functional ruthenium(II) complex. This innovative nanodevice holds promise as an efficient phosphorescent probe for both in vitro and in vivo imaging of living tumor cells.

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Liposomes, as a colloidal drug delivery system dating back to the 1960s, remain a focal point of extensive research and stand as a highly efficient drug delivery method. The amalgamation of technological and biological advancements has propelled their evolution, elevating them to their current status. The key attributes of biodegradability and biocompatibility have been instrumental in driving substantial progress in liposome development. Demonstrating a remarkable ability to surmount barriers in drug absorption, enhance stability, and achieve targeted distribution within the body, liposomes have become pivotal in pharmaceutical research. In this comprehensive review, we delve into the intricate details of liposomal drug delivery systems, focusing specifically on their pharmacokinetics and cell membrane interactions via fusion, lipid exchange, endocytosis etc. Emphasizing the nuanced impact of various liposomal characteristics, we explore factors such as lipid composition, particle size, surface modifications, charge, dosage, and administration routes. By dissecting the multifaceted interactions between liposomes and biological barriers, including the reticuloendothelial system (RES), opsonization, enhanced permeability and retention (EPR) effect, ATP-binding cassette (ABC) phenomenon, and Complement Activation-Related Pseudoallergy (CARPA) effect, we provide a deeper understanding of liposomal behaviour in vivo. Furthermore, this review addresses the intricate challenges associated with translating liposomal technology into practical applications, offering insights into overcoming these hurdles. Additionally, we provide a comprehensive analysis of the clinical adoption and patent landscape of liposomes across diverse biomedical domains, shedding light on their potential implications for future research and therapeutic developments.

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Cancer metastasis plays a major role in failure of therapeutic avenues against cancer. Owing to metastasis, nearly 70-80% of stage IV breast cancer patients lose their lives. Nanodrug delivery systems are playing a critical role in the therapy of metastatic cancer in the recent times. This paper reports the enhanced permeation and retention (EPR) based targeting of metastatic breast cancer using a novel nano lipo-polymeric system (PIR-Au NPs). The PIR-Au NPs demonstrated an increase in fluorescence by virtue of surface coating with gold, owing to the metal enhanced fluorescence phenomenon as reported in our earlier reports. Enhanced fluorescence of PIR-Au NPs was observed in murine mammary carcinoma cell line (4T1), as compared to free IR780 or IR780 loaded nanosystems (P-IR NPs), when incubated for same time at same concentrations, indicating its potential application for imaging and an enhanced bioavailability of IR780. Significant cell death was noted with photothermal mediated cytotoxicity in-vitro against breast cancer cells (MCF-7 and 4T1). An enhanced fluorescence was observed in the zebra fish embryos incubated with PIR-Au NPs. The enhanced permeation and retention (EPR) effect was seen with PIR-Au NPs in-vivo. A strong fluorescent signal was recorded in mice injected with PIR-Au NPs. The tumor tissue collected after 72 h, clearly showed a greater fluorescence as compared to other groups, indicating the plasmon enhanced fluorescence. We also demonstrated the EPR-based targeting of the PIR-Au NPs in-vivo by means of photothermal heat. This lipo-polymeric hybrid nanosystem could therefore be successfully applied for image-guided, passive-targeting to achieve maximum therapeutic benefits.

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The crossing of the blood-brain barrier (BBB) for conventional anticancer drugs is still a big challenge in treating glioma. The biomimetic nanoparticle delivery system has attracted increasing attention and has a promising future for crossing the BBB. Herein, we construct a multifunctional biomimetic nanoplatform using the erythrocyte membrane (EM) with the tumor-penetrating peptide iRGD (CRGDK/RGPD/EC) as a delivery, and the inner core loaded with the chemotherapeutic drug temozolomide (TMZ). The resulting biomimetic nanoparticle has perfect biocompatibility and stealth ability, which will provide more chances to escape the reticuloendothelial system (RES) entrapment, and increase the opportunity to enter the tumor site. Moreover, the decorated iRGD has been extensively used to actively targeting and deliver therapeutic agents across the BBB into glioma tissue. We show that this biomimetic delivery of TMZ with a diameter of 22 nm efficiently slowed the growth of glioblastoma multiforme (GBM) and increased the survival rate of the 30 d from 0% to 100%.

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Cannabidiol (CBD) is a promising drug candidate with pleiotropic pharmacological activity, whose low aqueous solubility and unfavorable pharmacokinetics have presented obstacles to its full clinical implementation. The rational design of nanocarriers, including niosomes for CBD encapsulation, can provide a plausible approach to overcoming these limitations. The present study is focused on exploring the feasibility of copolymer-modified niosomes as platforms for systemic delivery of CBD. To confer steric stabilization, the niosomal membranes were grafted with newly synthesized amphiphilic linear or star-shaped 3- and 4-arm star-shaped copolymers based on polyglycidol (PG) and poly(ε-caprolactone) (PCL) blocks. The niosomes were prepared by film hydration method and were characterized by DLS, cryo-TEM, encapsulation efficacy, and in vitro release. Free and formulated cannabidiol were further investigated for cytotoxicity and pro-apoptotic and anti-inflammatory activities in vitro in three human tumor cell lines. The optimal formulation, based on Tween 60:Span60:Chol (3.5:3.5:3 molar ration) modified with 2.5 mol% star-shaped 3-arm copolymer, is characterized by a size of 235 nm, high encapsulation of CBD (94%), and controlled release properties. Niosomal cannabidiol retained the antineoplastic activity of the free agent, but noteworthy superior apoptogenic and inflammatory biomarker-modulating effects were established at equieffective exposure vs. the free drug. Specific alterations in key signaling molecules, implicated in programmed cell death, cancer cell biology, and inflammation, were recorded with the niosomal formulations.

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Polymer-drug conjugates (PDCs) have shown great promise in enhancing the efficacy and safety of cancer therapy. These conjugates combine the advantageous properties of both polymers and drugs, leading to improved pharmacokinetics, controlled drug release, and targeted delivery to tumor tissues. This review provides a comprehensive overview of recent developments in PDCs for cancer therapy. First, various types of polymers used in these conjugates are discussed, including synthetic polymers, such as poly(↋-caprolactone) (PCL), D-α-tocopheryl polyethylene glycol (TPGS), and polyethylene glycol (PEG), as well as natural polymers such as hyaluronic acid (HA). The choice of polymer is crucial to achieving desired properties, such as stability, biocompatibility, and controlled drug release. Subsequently, the strategies for conjugating drugs to polymers are explored, including covalent bonding, which enables a stable linkage between the polymer and the drug, ensuring controlled release and minimizing premature drug release. The use of polymers can extend the circulation time of the drug, facilitating enhanced accumulation within tumor tissues through the enhanced permeability and retention (EPR) effect. This, in turn, results in improved drug efficacy and reduced systemic toxicity. Moreover, the importance of tumor-targeting ligands in PDCs is highlighted. Various ligands, such as antibodies, peptides, aptamers, folic acid, herceptin, and HA, can be incorporated into conjugates to selectively deliver the drug to tumor cells, reducing off-target effects and improving therapeutic outcomes. In conclusion, PDCs have emerged as a versatile and effective approach to cancer therapy. Their ability to combine the advantages of polymers and drugs offers enhanced drug delivery, controlled release, and targeted treatment, thereby improving the overall efficacy and safety of cancer therapies. Further research and development in this field has great potential to advance personalized cancer treatment options.

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The low distribution of hydrophobic anticancer drugs in patients is one of the biggest limitations during conventional chemotherapy. SDS-based polyelectrolyte multicore nanocarriers (NCs) prepared according to the layer by layer (LbL) procedure can release paclitaxel (PTX), and selectively kill cancer cells. Our main objective was to verify the antitumor properties of PTX-loaded NCs and to examine whether the drug encapsulated in these NCs retained its cytotoxic properties. The cytotoxicity of the prepared nanosystems was tested on MCF-7 and MDA-MB-231 tumour cells and the non-cancerous HMEC-1 cell line in vitro. Confocal microscopy, spectrophotometry, spectrofluorimetry, flow cytometry, and RT PCR techniques were used to define the typical hallmarks of apoptosis. It was demonstrated that PTX encapsulated in the tested NCs exhibited similar cytotoxicity to the free drug, especially in the triple negative breast cancer model. Moreover, SDS/PLL/PTX and SDS/PLL/PGA/PTX significantly reduced DNA synthesis. In addition, PTX-loaded NCs triggered apoptosis and upregulated the transcription of Bax, AIF, cytochrome-c, and caspase-3 mRNA. Our data demonstrate that these novel polyelectrolyte multicore NCs coated with PLL or PLL/PGA are good candidates for delivering PTX. Our discoveries have prominent implications for the possible choice of newly synthesized, SDS-based polyelectrolyte multicore NCs in different anticancer therapeutic applications.

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Immunotherapy has developed rapidly in solid tumors, especially in the areas of blocking inhibitory immune checkpoints and adoptive T-cell transfer for immune regulation. Many patients benefit from immunotherapy. However, the response rate of immunotherapy in the overall population are relatively low, which depends on the characteristics of the tumor and individualized patient differences. Moreover, the occurrence of drug resistance and adverse reactions largely limit the development of immunotherapy. Recently, the emergence of nanodrug delivery systems (NDDS) seems to improve the efficacy of immunotherapy by encapsulating drug carriers in nanoparticles to precisely reach the tumor site with high stability and biocompatibility, prolonging the drug cycle of action and greatly reducing the occurrence of toxic side effects. In this paper, we mainly review the advantages of NDDS and the mechanisms that enhance conventional immunotherapy in solid tumors, and summarize the recent advances in NDDS-based therapeutic strategies, which will provide valuable ideas for the development of novel tumor immunotherapy regimen.

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The characteristics of the primary tumor blood vessels and the tumor microenvironment drive the enhanced permeability and retention (EPR) effect, which confers an advantage towards enhanced delivery of anti-cancer nanomedicine and has shown beneficial effects in preclinical models. Increased vascular permeability is a landmark feature of the tumor vessels and an important driver of the EPR. The main focus of this review is the endothelial regulation of vascular permeability. We discuss current challenges of targeting vascular permeability towards clinical translation and summarize the structural components and mechanisms of endothelial permeability, the principal mediators and signaling players, the targeted approaches that have been used and their outcomes to date. We also critically discuss the effects of the tumor-infiltrating immune cells, their interplay with the tumor vessels and the impact of immune responses on nanomedicine delivery, the impact of anti-angiogenic and tumor-stroma targeting approaches, and desirable nanoparticle design approaches for greater translational benefit.

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Over the past few decades, the enhanced permeability and retention (EPR) effect of nanomedicine has been a crucial phenomenon in targeted cancer therapy. Specifically, understanding the EPR effect has been a significant aspect of delivering anticancer agents efficiently to targeted tumors. Although the therapeutic effect has been demonstrated in experimental models using mouse xenografts, the clinical translation of the EPR effect of nanomedicine faces several challenges due to dense extracellular matrix (ECM), high interstitial fluid pressure (IFP) levels, and other factors that arise from tumor heterogeneity and complexity. Therefore, understanding the mechanism of the EPR effect of nanomedicine in clinics is essential to overcome the hurdles of the clinical translation of nanomedicine. This paper introduces the basic mechanism of the EPR effect of nanomedicine, the recently discussed challenges of the EPR effect of nanomedicine, and various strategies of recent nanomedicine to overcome the limitations expected from the patients' tumor microenvironments.

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Targeted nanotheranostic systems offer significant benefits due to the integration of diagnostic and therapeutic functionality, promoting personalized medicine. In recent years, prostate-specific membrane antigen (PSMA) has emerged as an ideal theranostic target, fueling multiple new drug approvals and changing the standard of care in prostate cancer (PCa). PSMA-targeted nanosystems such as self-assembled nanoparticles (NPs), liposomal structures, water-soluble polymers, dendrimers, and other macromolecules are under development for PCa theranostics due to their multifunctional sensing and therapeutic capabilities. Herein, we discuss the significance and up-to-date development of "PSMA-targeted nanocarrier systems for radioligand imaging and therapy of PCa". The review also highlights critical parameters for designing nanostructured radiopharmaceuticals for PCa, including radionuclides and their chelators, PSMA-targeting ligands, and the EPR effect. Finally, prospects and potential for clinical translation is discussed.

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Nanocarriers passively accumulate in solid tumors through irregular wide fenestrations in neovasculature and increased retention due to poor lymphatic drainage, a phenomenon termed the enhanced permeation and retention (EPR) effect. Although several preclinical reports have described the role of EPR in nanomedicine, its role in human solid tumor is obscure. There are several distinct factors for tumors in mice versus humans, including size, heterogeneity and nanomedicine pharmacokinetics. This review focuses on preclinical and clinical studies demonstrating the role of the EPR effect and passive targeting. The article illustrates the gaps that limit clinical effectiveness of the EPR effect and elaborates strategies to boost its efficiency, relaying future clinical outcomes for designing clinically applicable EPR-based nanomedicine.

Unlike healthy organ vasculature in organs, solid tumor vasculature is leaky with poor lymphatic drainage. Nanoparticles <200 nm are reported to be selectively taken up in the tumor due to this tumor physiology, a process referred to as the enhanced permeation and retention (EPR) effect. Despite lots of preclinical evidence, there is lack of clinical success observed for EPR effect in human tumors. There are several factors responsible for this poor preclinical to clinical rendition of nanomedicine delivery to tumors by EPR effect. We have highlighted key differences between murine and human tumor models as well as listed effective approaches to boost the EPR effect in nanomedicine. These strategies will bridge the gaps that limit clinical translation of EPR-based nanomedicine and lay the groundwork to design effective anticancer therapies.

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The use of pH-responsive polymeric micelles is a promising approach to afford the targeted, pH-mediated delivery of hydrophobic drugs within the low-pH tumour milieu and intracellular organelles of cancer cells. However, even for a common pH-responsive polymeric micelle system-e.g., those utilising poly(ethylene glycol)-b-poly(2-vinylpyridine) (PEG-b-PVP) diblock copolymers-there is a lack of available data describing the compatibility of hydrophobic drugs, as well as the relationships between copolymer microstructure and drug compatibility. Furthermore, synthesis of the constituent pH-responsive copolymers generally requires complex temperature control or degassing procedures that limit their accessibility. Herein we report the facile synthesis of a series of diblock copolymers via visible-light-mediated photocontrolled reversible addition-fragmentation chain-transfer polymerisation, with a constant PEG block length (90 repeat units (RUs)) and varying PVP block lengths (46-235 RUs). All copolymers exhibited narrow dispersity values (D ≤ 1.23) and formed polymeric micelles with low polydispersity index (PDI) values (typically <0.20) at physiological pH (7.4), within a suitable size range for passive tumour targeting (<130 nm). The encapsulation and release of three hydrophobic drugs (cyclin-dependent kinase inhibitor (CDKI)-73, gossypol, and doxorubicin) were investigated in vitro at pH 7.4-4.5 to simulate drug release within the tumour milieu and cancer cell endosome. Marked differences in drug encapsulation and release were observed when the PVP block length was increased from 86 to 235 RUs. With a PVP block length of 235 RUs, the micelles exhibited differing encapsulation and release properties for each drug. Minimal release was observed for doxorubicin (10%, pH 4.5) and CDKI-73 exhibited moderate release (77%, pH 4.5), whereas gossypol exhibited the best combination of encapsulation efficiency (83%) and release (91% pH 4.5) overall. These data demonstrate the drug selectivity of the PVP core, where both the block molecular weight and hydrophobicity of the core (and accordingly the hydrophobicity of the drug) have a significant effect on drug encapsulation and release. These systems remain a promising means of achieving targeted, pH-responsive drug delivery-albeit for select, compatible hydrophobic drugs-which warrants their further investigation to develop and evaluate clinically relevant micelle systems.

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The delivery of chemotherapies to brain tumors faces the difficult task of crossing the blood-brain barrier (BBB).1-4 The brain capillary endothelial cells (BCECs) along with other cell lines, such as astrocytes and pericytes, form the BBB. This highly selective semipermeable barrier separates the blood from the brain parenchyma. The BBB controls the movement of drug molecules in a selective manner5 and maintains central nervous system (CNS) homeostasis. Depending on the properties of drugs such as their hydrophilic-lipophilic balance (HLB), some can cross the BBB through passive diffusion.6 However, this approach alone has not led to successful drug developments due to low net diffusion rates and systemic toxicity. Although the use of nanomedicine has been proposed to overcome these drawbacks, many recent studies still rely on the so-called 'enhanced permeability and retention (EPR)' effect though there is a realization in the field of drug delivery that EPR effect may not be sufficient for successful drug delivery to brain tumors. Since, compared to many other solid tumors, brain tumors pose additional challenges such as more restrictive blood-tumor barrier as well as the well-developed lymphatic drainage, the selection of functional moieties on the nanocarriers under consideration must be carried out with care to propose better solutions to this challenge.

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The principle of enhanced permeability and retention (EPR) effect has been used to design anti-cancer nanomedicines over decades. However, it is being challenged due to the poor clinical outcome of nanoparticles and controversial physiological foundation. Herein, we use a near-infrared-II (1000-1700 nm, NIR-II) fluorescence probe BPBBT to investigate the pathway for the entry of human serum albumin-bound nanoparticles (BPBBT-HSA NPs) into tumor compared with BPBBT micelles with phospholipid-poly (ethylene glycol) of the similar particle size about 110 nm. The plasma elimination half-life of BPBBT micelles was 2.8-fold of that of BPBBT-HSA NPs. However, the area under the BPBBT concentration in tumor-time curve to 48 h post-injection (AUCtumor0→48h) of BPBBT-HSA NPs was 7.2-fold of that of BPBBT micelles. The intravital NIR-II fluorescence microscopy revealed that BPBBT-HSA NPs but not BPBBT micelles were transported from the tumor vasculature into tumor parenchyma with high efficiency, and endocytosed by the tumor cells within 3 h post-injection in vivo. This effect was blocked by cross-linking BPBBT-HSA NPs to denature HSA, resulting in the AUCtumor0→48h decreased to 22% of that of BPBBT-HSA NPs. Our results demonstrated that the active process of endothelial transcytosis is the dominant pathway for albumin-bound nanoparticles' entry into tumor.

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Objective: To investigate the effect of hypertension on the (enhanced permeability and retention, EPR) effect induced by polymer nanomicelles in renal cell carcinoma in vitro. Methods: A total of 80 patients with renal cell carcinoma treated at the Department of Urology Surgery in the Dept. of Urology of the Affiliated Hospital of Hebei University from Oct. 2019 to Oct. 2020, were analyzed retrospectively. The hypertension group (experimental group) included 40 patients, and the normal blood pressure group (control group) included 40 patients. The diagnosis of renal clear cell carcinoma was confirmed by preoperative auxiliary examinations, such as ultrasonography and CT combined with postoperative pathological analysis. All patients underwent laparoscopic radical nephrectomy for renal cell carcinoma. Polymer nanomicelles (loaded with prolonium iodide) were perfused into the resected kidney specimens within the specified time. The iodine enrichment of polymer nanomicelles in renal tumors was assessed by CT scanning. The peak EPR effect and the time to the peak were statistically compared between the two groups. Results: No significant differences were found in age, sex, location of kidney disease, tumor location or tumor size between the two groups (p> 0.05). The peak (χ̄±S) of the EPR effect in experimental group was 3.60±0.95 ug/cm3 and 3.01±0.96 ug/cm3 in control group, respectively. There was significant difference between the two groups (p< 0.05). The time to the peak of the EPR effect was 3.76±0.75 h in experimental group and 3.82±0.93 hour in control group, respectively. No statistically significant difference was found in the time to the peak of the EPR effect between the two groups (p> 0.05). Conclusion: Hypertension has a certain effect on the EPR effect induced by polymer nanomicelles in renal cell carcinoma in vitro.

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Multidrug resistance (MDR) reduces the efficacy of chemotherapy. Besides inducing the expression of drug efflux pumps, chemotherapy treatment alters the composition of the tumor microenvironment (TME), thereby potentially limiting tumor-directed drug delivery. To study the impact of MDR signaling in cancer cells on TME remodeling and nanomedicine delivery, we generated multidrug-resistant 4T1 triple-negative breast cancer (TNBC) cells by exposing sensitive 4T1 cells to gradually increasing doxorubicin concentrations. In 2D and 3D cell cultures, resistant 4T1 cells are presented with a more mesenchymal phenotype and produced increased amounts of collagen. While sensitive and resistant 4T1 cells showed similar tumor growth kinetics in vivo, the TME of resistant tumors was enriched in collagen and fibronectin. Vascular perfusion was also significantly increased. Fluorophore-labeled polymeric (∼10 nm) and liposomal (∼100 nm) drug carriers were administered to mice with resistant and sensitive tumors. Their tumor accumulation and penetration were studied using multimodal and multiscale optical imaging. At the whole tumor level, polymers accumulate more efficiently in resistant than in sensitive tumors. For liposomes, the trend was similar, but the differences in tumor accumulation were insignificant. At the individual blood vessel level, both polymers and liposomes were less able to extravasate out of the vasculature and penetrate the interstitium in resistant tumors. In a final in vivo efficacy study, we observed a stronger inhibitory effect of cellular and microenvironmental MDR on liposomal doxorubicin performance than free doxorubicin. These results exemplify that besides classical cellular MDR, microenvironmental drug resistance features should be considered when aiming to target and treat multidrug-resistant tumors more efficiently.

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Evidence is mounting that there is a significant gap between the antitumor efficacy of nanodrugs in preclinical mouse tumor models and in clinical human tumors, and that differences in tumor models are likely to be responsible for this gap. Herein, we investigated the enhanced permeability and retention (EPR) effect in mouse lung cancer models with different tumor growth rates, volumes and locations, and analyzed the nanodrug tumor targeting behaviors limited by tumor vascular pathophysiological characteristics in various tumor models. The results showed that the fast-growing tumors were characterized by lower vascular tight junctions, leading to higher vascular paracellular transport activity and nanodrug tumor accumulation. The paracellular transport activity increased with the growth of tumor, but the vascular density and transcellular transport activity decreased, and as a result, the average tumor accumulation of passive targeting nanodrugs decreased. Orthotopic tumors were rich in blood vessels, but had low vascular transcellular and paracellular transport activities, making it difficult for nanodrug accumulation in orthotopic tumors via passive targeting strategies. The antitumor efficacy of passive targeting nanodrugs in various lung cancer-bearing mice validated the aforementioned nanodrug accumulation behavior, and nanodrugs based on the angiogenesis-tumor sequential targeting strategy achieved obviously improved efficacy in orthotopic lung cancer-bearing mice. These results suggest that the EPR effect varies in different tumor models and should not be used as a universal targeting strategy for antitumor nanodrugs. Besides, attention should be paid to the animal tumor models in the evaluation of nanodrugs so as to avoid exaggerating the antitumor efficacy.

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In this study, we developed a nanoformulation of 5-aminolevulinic acid (5-ALA) for tumor-targeted photodynamic therapy, in which 5-ALA was conjugated with a biocompatible polymer N-(2-hydroxypropyl)methacrylamide (HPMA) through the hydrazone bond, i.e., P-ALA. P-ALA behaves as the nano-sized molecule with an average size of 5.5 nm in aqueous solution. P-ALA shows a largely increased release rate in acidic pH than physiological pH, suggesting the rapid release profile in acidic tumor environment. P-ALA did not show apparent cytotoxicity up to 0.1 mg/ml, however, under light irradiation, remarkable cell death was induced with the IC50 of 20-30 µg/ml. More importantly, we found significantly higher tumor accumulation of P-ALA than 5-ALA which benefit from its nano-size by taking advantage of the enhanced permeability and retention (EPR) effect. Consequently, P-ALA exhibited much improved in vivo antitumor efficacy without any apparent side effects. We thus anticipate the application of P-ALA as a nano-designed photosensitizer for anticancer photodynamic therapy.

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The enhanced permeability and retention effect (EPR effect) is a crucial phenomenon for understanding the pathophysiological characteristics of blood vasculature and microenvironments in solid tumors. It is also an essential concept for designing anticancer drugs that can be selectively delivered into tumor tissue via the unique extravasation and retention mechanism for macromolecular drugs. As tumor vasculature is highly heterogeneous, the intensities of the EPR effect vary according to the types and locations of solid tumors in different species. However, the EPR effect is universally observed in a broad spectrum of solid tumors in human cancer as well as experimental animal tumor models. The matter is how to utilize the EPR effect for drug design and clinical application. Many hypotheses were proposed and tested to enhance the EPR effect in solid tumors in order to increase the efficacy of drug delivery. However, we should focus on increasing the blood flow in tumors so that more drugs can be perfused and accumulated inside tumor tissue and execute anticancer activities. Angiotensin II co-administration and the approach of intratumor arterial infusion should be considered to achieve selective tumor tissue perfusion for nanodrugs.