Physical activity and the risk of non-Hodgkin lymphoma subtypes: A pooled analysis.

Non-Hodgkin lymphoma (NHL) is composed of a heterogeneous collection of subtypes with considerable differences in genetics, biology and aetiology. Studies to date on physical activity and NHL risk have not had sufficient sample size to evaluate whether associations differ by subtype. We pooled data from nine case-control studies to examine the association between moderate-to-vigorous intensity physical activity (MVPA) and risk of NHL overall and by subtype (diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma, marginal zone lymphoma and mature T-cell lymphoma). A total of 5653 cases and 9115 controls were included in the pooled analysis. Physical activity was harmonised across nine studies and modelled as study-specific tertiles. Multinomial logistic regression was used to estimate the association between physical activity and NHL, adjusting for confounders. The overall odds of NHL was 13% lower among participants in the most active tertile of MVPA compared to the least active tertile (adjusted odds ratio = 0.87, 95% CI = 0.80, 0.95). Similar decreases were observed across NHL subtypes. In summary, in this pooled analysis of case-control studies, physical activity was associated with a modest risk reduction for each NHL subtype examined and with overall NHL.

Does a Multiple Myeloma Polygenic Risk Score Predict Overall Survival of Patients with Myeloma?

BACKGROUND: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. METHODS: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. RESULTS: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. CONCLUSIONS: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. IMPACT: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans.

Monoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10-29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10-63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10-5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.

Vaccination History and Risk of Lymphoma and Its Major Subtypes.

BACKGROUND: Vaccinations have been hypothesized to play a role in lymphoma etiology, but there are few studies, mixed results, and limited data on lymphoma subtypes. Herein, we investigate the association of vaccinations with risk of major lymphoma subtypes. METHODS: We studied 2,461 lymphoma cases and 2,253 controls enrolled from 2002 to 2014. Participants self-reported history of vaccinations against hepatitis A, hepatitis B, yellow fever, and influenza. Polytomous logistic regression was used to estimate OR and 95% confidence intervals (CI), adjusting for potential confounders. RESULTS: After multivariable adjustment, vaccination against influenza was inversely associated with lymphoma (OR = 0.82; 95% CI, 0.66-1.02), which was stronger for last vaccination 1+ years before enrollment (OR = 0.71; 95% CI, 0.56-0.91) and for >5 influenza vaccinations (OR = 0.56; 95% CI, 0.46-0.68). Ever vaccination against hepatitis A (OR = 0.81; 95% CI, 0.66-1.00) but not hepatitis B (OR = 0.97; 95% CI, 0.81-1.18) was associated with lymphoma risk, although more recent vaccinations were inversely associated with lymphoma risk for both hepatitis A (<6 years before enrollment, OR = 0.56; 95% CI, 0.40-0.77) and hepatitis B (<9 years before enrollment, OR = 0.72; 95% CI, 0.55-0.93). Ever vaccination against yellow fever was inversely associated with risk (OR = 0.73; 95% CI, 0.55-0.96), and this did not vary by time since last vaccination. Although there was no overall statistical evidence for heterogeneity of vaccination history by lymphoma subtype, the only statistically significant inverse associations were observed for influenza and yellow fever vaccinations with diffuse large B-cell and follicular lymphoma. CONCLUSIONS: Selected vaccinations were inversely associated with lymphoma risk, with time since last vaccination relevant for some of these vaccines. IMPACT: Vaccinations against hepatitis A, hepatitis B, yellow fever, and influenza are unlikely to increase lymphoma risk.

Body mass index and survival of patients with lymphoma.

The impact of body mass index (BMI) on survival in lymphoma remains controversial. We leveraged a prospective cohort of lymphoma patients enrolled to SPORE Molecular Epidemiology Resource between 2002 and 2015 to assess the association of BMI before diagnosis, BMI at diagnosis, and BMI change over time with lymphoma-specific survival (LSS). A total of 4009 lymphoma patients (670 diffuse large B-cell lymphoma (DLBCL), 689 follicular lymphoma (FL), 1018 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and 1632 other subtypes) were included. Significantly shorter LSS after diagnosis was observed for FL patients who were obese before diagnosis (HR: 3.02, 95%CI: 1.43-6.41, p=.004) and for those with a ≥ 5% increase in BMI from diagnosis to 3-year follow-up (HR: 3.53, 95%CI: 1.22-10.2, p=.020). In contrast, obesity prior to or at the time of diagnosis was not associated with LSS in DLBCL and CLL/SLL. The impact of weight control after diagnosis in FL patient warrants investigation.

The association of health behaviors with quality of life in lymphoma survivors.

The impact of change in health behaviors (physical activity [PA], alcohol and smoking) on quality of life (QOL) in lymphoma survivors is not well understood. We evaluated the associations of health behaviors with QOL domains at diagnosis and at 3-year follow-up (FU3) in 2805 lymphoma survivors. We report clinically significant QOL score differences, defined as scores that exceeded a minimally important difference threshold and were statistically significant. Current smoking was associated with lower QOL at baseline (p < 0.01) and at FU3 (p < 0.01). Meeting the American Cancer Society PA guidelines was associated with better functional wellbeing and overall QOL at FU3 (p < 0.01). An increase in PA from baseline to FU3 was associated with improvement in physical, functional wellbeing and overall QOL at FU3 compared to baseline (p < 0.01). Thus, QOL in lymphoma survivors is associated with their health behaviors and active interventions to promote positive lifestyle changes in lymphoma survivors are needed.

Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance.

So far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879), we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Heritability and genetic estimates yielded 17% (standard error [SE] ±0.04) and 15% (SE ±0.11) for MM and MGUS risk, respectively, and a 55% (SE ±0.30) genetic correlation. The MM-PRS was associated with risk of MM when assessed continuously (odds ratio [OR], 1.17 per SD; 95% confidence interval [CI], 1.13-1.21) or categorically (OR, 1.70; 95% CI, 1.38-2.09 for highest; OR, 0.71; 95% CI, 0.55-0.90 for lowest compared with middle quintile). The MM-PRS was similarly associated with MGUS (OR, 1.19 per SD; 95% CI, 1.14-1.26 as a continuous measure, OR, 1.77, 95%CI: 1.29-2.43 for highest and OR, 0.70, 95%CI: 0.50-0.98 for lowest compared with middle quintile). MM and MGUS associations did not differ by age, sex, or MM immunoglobulin isotype. We validated a 23-SNP MM-PRS in an independent series of MM cases and provide evidence for its association with MGUS. Our results suggest shared common genetic susceptibility to MM and MGUS.

Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis.

Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10-94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10-30) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10-16). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.

Rationale and Design of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma Subtypes Project.

BACKGROUND: Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design. METHODS: We pooled individual-level data from 20 case-control studies (17471 NHL cases, 23096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control. RESULTS: The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes. CONCLUSIONS: The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology.

Fatty acids found in dairy, protein and unsaturated fatty acids are associated with risk of pancreatic cancer in a case-control study.

Although many studies have investigated meat and total fat in relation to pancreatic cancer risk, few have investigated dairy, fish and specific fatty acids (FAs). We evaluated the association between intake of meat, fish, dairy, specific FAs and related nutrients and pancreatic cancer. In our American-based Mayo Clinic case-control study 384 cases and 983 controls frequency matched on recruitment age, race, sex and residence area (Minnesota, Wisconsin or Iowa, USA) between 2004 and 2009. All subjects provided demographic information and completed 144-item food frequency questionnaire. Logistic regression-calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) were adjusted for age, sex, cigarette smoking, body mass index and diabetes mellitus. Significant inverse association (trend p-value < 0.05) between pancreatic cancer and the groupings (highest vs. lowest consumption quintile OR [95% CI]) was as follows: meat replacement (0.67 [0.43-1.02]), total protein (0.58 [0.39-0.86]), vitamin B12 (0.67 [0.44, 1.01]), zinc (0.48 [0.32, 0.71]), phosphorus (0.62 [0.41, 0.93]), vitamin E (0.51 [0.33, 0.78]), polyunsaturated FAs (0.64 [0.42, 0.98]) and linoleic acid (FA 18:2) (0.62 [0.40-0.95]). Increased risk associations were observed for saturated FAs (1.48 [0.97-2.23]), butyric acid (FA 4:0) (1.77 [1.19-2.64]), caproic acid (FA 6:0) (2.15 [1.42-3.27]), caprylic acid (FA 8:0) (1.87 [1.27-2.76]) and capric acid (FA 10:0) (1.83 [1.23-2.74]). Our study suggests that eating a diet high in total protein and certain unsaturated FAs is associated with decreased risk of developing pancreatic cancer in a dose-dependent manner, whereas fats found in dairy increase risk.

Polymorphisms in metabolism/antioxidant genes may mediate the effect of dietary intake on pancreatic cancer risk.

OBJECTIVES: A source of variation for inconsistent dietary-pancreatic cancer associations may be individuals carrying constitutional metabolism/antioxidant gene variants that differentially benefit compared to homozygous individuals. Seventy-six tag single-nucleotide polymorphisms were genotyped in 13 candidate genes to test differential associations with pancreatic adenocarcinoma. METHODS: A clinic-based case-control design was used to rapidly ascertain 251 cases and 970 frequency matched controls who provided blood samples and completed a 144-item food frequency questionnaire. Single-nucleotide polymorphisms were evaluated using a dominant genetic model and dietary categories split on controls' median intake. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusted for potential confounders. RESULTS: Significant increased associations (Bonferroni corrected P ≤ 0.0007) were observed for carriers of greater than or equal to 1 minor allele for rs3816257 (glucosidase, α; acid [GAA]) and lower intake of deep-yellow vegetables (1.90 [1.28-2.83]); and carriers of no minor allele for rs12807961 (catalase [CAT]) and high total grains intake (2.48 [1.50-4.09]), whereas those with greater than or equal to 1 minor allele had a decreasing slope (across grains). The reference group was no minor alleles with low dietary intake. CONCLUSIONS: Interindividual variation in metabolism/antioxidant genes could interact with dietary intake to influence pancreatic cancer risk.

pH-dependent stability of creatine ethyl ester: relevance to oral absorption.

Creatine ethyl ester hydrochloride (CEE) was synthesized as a prodrug of creatine (CRT) to improve aqueous solubility, gastrointestinal permeability, and ultimately the pharmacodynamics of CRT. We used high-performance liquid chromatography (HPLC) and proton nuclear magnetic resonance (NMR) to characterize the pH-dependent stability of CEE in aqueous solution and compared the permeability of CEE to CRT and creatinine (CRN) across Caco-2 human epithelial cell monolayers and transdermal permeability across porcine skin. CEE was most stable in a strongly acidic condition (half-life = 570 hours at pH 1.0) where it undergoes ester hydrolysis to CRT and ethanol. At pH ≥ 1.0, CEE cyclizes to CRN with the logarithm of the first order rate constant increasing linearly with pH. Above pH 8.0 (half-life = 23 sec) the rate of degradation was too rapid to be determined. The rate of degradation of CEE in cell culture media and simulated intestinal fluid (SIF) was a function of pH and correlated well with the stability in aqueous buffered solutions. The permeability of CEE across Caco-2 monolayers and porcine skin was significantly greater than that of CRT or CRN. The stability of CEE in acidic media together with its improved permeability suggests that CEE has potential for improved oral absorption compared to CRT.

Meat-related mutagens and pancreatic cancer: null results from a clinic-based case-control study.

BACKGROUND: Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. The study objective was to evaluate risk of pancreatic cancer associated with meat preparation methods and meat-related mutagen consumption using a clinic-based case-control design. METHODS: There were 384 cases and 983 controls; subjects provided demographic information and completed a 144-item food frequency questionnaire, which was used to estimate meat mutagen intake using the National Cancer Institute's CHARRED database (Bethesda, MD). Logistic regression was used to calculate ORs and 95% confidence intervals (CI), adjusted for factors including age, sex, cigarette smoking, body mass index, and diabetes mellitus. RESULTS: Overall, the findings were null with respect to meat mutagen intake and pancreatic cancer. CONCLUSIONS: The results do not support an association between well-done meat or meat-related mutagen intake and pancreatic cancer and contrast with generally increased risks reported in previous studies. IMPACT: These data contribute to evidence about pancreatic cancer and potentially carcinogenic compounds in meat.

Nutrients from fruit and vegetable consumption reduce the risk of pancreatic cancer.

PURPOSE: Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. Our objective was to evaluate the risk of pancreatic cancer associated with nutrients found in fruits and vegetables and nutrient supplementation using a clinic-based case-control design. METHODS: Our study included 384 rapidly ascertained cases and 983 controls frequency-matched on age at time of recruitment (in 5-year increments), race, sex, and region of residence. All subjects provided demographic information and completed a 144-item food frequency questionnaire in which they reported no change to their diet within 5 years prior to entering the study. Logistic regression was used to calculate odds ratios and 95 % confidence intervals, adjusted for age, sex, smoking, body mass index, energy intake, and alcohol consumption. RESULTS: Results show a significant (trend p value < 0.05) inverse association between pancreatic cancer and nutrient/supplement groupings in a dose-dependent manner including magnesium, potassium, selenium, alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein and zeaxanthin, niacin, total alpha-tocopherol, total vitamin A activity, vitamin B6, and vitamin C. Adjusting for diabetes or total sugar intake did not result in significant changes. CONCLUSION: We conclude that most nutrients obtained through consumption of fruits and vegetables may reduce the risk of developing pancreatic cancer.

Fruit and vegetable consumption is inversely associated with having pancreatic cancer.

OBJECTIVE: Studies on fruit, vegetable, fiber, and grain consumption and pancreatic cancer risk are inconclusive. We used a clinic-based case-control study specifically designed to address limitations of both cohort and case-control studies to examine the relationship. METHODS: Participants were excluded who reported changing their diet within 5 years prior to study entry. And 384 rapidly ascertained cases and 983 controls (frequency matched on age (±5 years), race, sex, and residence) completed epidemiologic surveys and 144-item food frequency questionnaires. Odds ratios (OR) and 95% confidence intervals were calculated using logistic regression adjusted for age, sex, smoking, body mass index, energy intake, and alcohol consumption. RESULTS: Comparing highest to lowest quintiles, we observed significant inverse associations (OR < 0.8) with significant trends (p (trend) < 0.05) for citrus, melon, and berries, other fruits, dark green vegetables, deep yellow vegetables, tomato, other vegetables, dry bean and pea, insoluble fiber, soluble fiber, whole grains, and orange/grapefruit juice, and an increased association with non-whole grains. Results were similar after adjusting for diabetes or total sugar intake. CONCLUSIONS: We provide evidence that lower consumption of fruits, vegetables, whole grains, and fiber is associated with having pancreatic cancer. This may have a role in developing prevention strategies.

Aspirin, nonsteroidal anti-inflammatory drugs, acetaminophen, and pancreatic cancer risk: a clinic-based case-control study.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAID) show indisputable promise as cancer chemoprevention agents. However, studies have been inconsistent as to whether aspirin has a protective effect in development of pancreatic cancer. To further evaluate the association between aspirin, NSAID, and acetaminophen use with pancreatic cancer risk, we used a clinic-based case-control study of 904 rapidly ascertained histologically or clinically documented pancreatic ductal adenocarcinoma cases, and 1,224 age- and sex-matched healthy controls evaluated at Mayo Clinic from April 2004 to September 2010. Overall, there is no relationship between non-aspirin NSAID or acetaminophen use and risk of pancreatic cancer. Aspirin use for 1 d/mo or greater was associated with a significantly decreased risk of pancreatic cancer (OR = 0.74, 95% CI: 0.60-0.91, P = 0.005) compared with never or less than 1 d/mo. Analysis by frequency and frequency-dosage of use categories showed reduced risk (P = 0.007 and 0.022, respectively). This inverse association was also found for those who took low-dose aspirin for heart disease prevention (OR = 0.67, 95% CI: 0.49-0.92, P = 0.013). In subgroup analyses, the association between aspirin use and pancreatic cancer was not significantly affected by pancreatic cancer stage, smoking status, or body mass index. Our data suggest that aspirin use, but not non-aspirin NSAID use, is associated with lowered risk of developing pancreatic cancer.

Enhanced cellular association of paclitaxel delivered in chitosan-PLGA particles.

We have previously demonstrated that the cellular association, cytotoxicity, and in vivo anti-tumor efficacy of paclitaxel are significantly greater when delivered in PLGA microparticles compared to nanoparticles. The purpose of this research is to test the hypothesis that mucoadhesive chitosan promotes adhesion of PLGA particles to mucus on the tumor epithelium, resulting in enhanced cellular association and cytotoxicity of paclitaxel. PLGA particles containing paclitaxel or Bodipy(®) were prepared and chitosan was either adsorbed or chemically conjugated to the particle surface. The cellular association and cytotoxicity of paclitaxel in 4T1 cells was determined. A 4-10 fold increase in cellular association of paclitaxel was observed when chitosan was adsorbed or conjugated to the PLGA particles. Chitosan-conjugated PLGA microparticles were most cytotoxic with an IC(50) value of 0.77 µM. Confocal microscopy demonstrated that chitosan-PLGA microparticles adhered to the surface of 4T1 cells. Pretreatment of either 4T1 cells or chitosan-PLGA particles with mucin resulted in significant increase in cellular association of paclitaxel. A linear correlation was established between theoretical amount of chitosan used and experimentally determined amount of chitosan adsorbed or conjugated to PLGA nanoparticles. In conclusion, cellular association and cytotoxicity of paclitaxel was significantly enhanced when delivered in chitosan-PLGA particles.

Comparison of anti-tumor efficacy of paclitaxel delivered in nano- and microparticles.

This research compares the anti-tumor efficacy of paclitaxel delivered intratumorally in PLGA nanoparticles, microparticles, or the commercial Paclitaxel Injection((R)). The hypothesis of the research is that larger PLGA microparticles adhere to mucus on the cell surface, release paclitaxel locally, and enhance cellular association of paclitaxel. PLGA-paclitaxel particles of mean diameters 315 nm, 1 microm, and 10 microm were prepared and their drug content, in vitro release, and cellular association of paclitaxel into 4T1 cells quantified. These particles were injected intratumorally into tumor xenografts, and the tumor volumes monitored over 13 days. Mean tumor volumes of the groups that received placebo and the 315 nm nanoparticles increased 2 and 1.5 times, respectively. Tumor growth was arrested in groups that received 1 microm and 10 microm microparticles. Additional cell culture studies were performed to test the hypothesis. The size-dependent increase in cellular concentration of paclitaxel was independent of duration of incubation of PLGA particles with 4T1 cells, and was enhanced 1.5 times by coating the particles or 4T1 cells with mucin. These particles were not internalized by clathrin-mediated endocytosis or macropinocytosis. In conclusion, PLGA microparticles sustained drug release, increased cellular concentration, and enhanced anti-tumor efficacy of paclitaxel compared to nanoparticles and Paclitaxel Injection.